Quinoline or quinazoline derivatives inhibiting auto-phosphorylation of fibroblast growth factor receptors

ABSTRACT

An objective of the present invention is to provide novel compounds which have inhibitory activity against autophosphorylation of an FGF receptor family and, when orally or intraveneously administered, can suppress the growth of cancer cells. The compounds of the present invention are represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof:  
                 
 
wherein X represents CH or N; Z represents O or S; Q represents NR 10 , CR 11 R 2 , carbonyl, O, S(═O)m, wherein m is 0 to 2, or urea; R 1  to R 3  each independently represent H, OH, halogen, nitro, amino, alkyl, alkoxy or the like in which the alkyl and alkoxy groups are optionally substituted; R 4  represents H; R 5  to R 8  each independently represent H, halogen, alkyl, or alkoxy; and R 9  represents an optionally substituted carbocyclic or heterocyclic group.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to quinoline derivatives and quinazolinederivatives which have antitumor activity. More particularly, thepresent invention relates to quinoline derivatives and quinazolinederivatives which have inhibitory activity against theautophosphorylation of fibroblast growth factor receptors and haveinhibitory activity against abnormal cell proliferation.

2. Background Art

Growth factors such as epithelial growth factors, platelet-derivedgrowth factors, insulin-like growth factors, and basic fibroblast growthfactors (hereinafter abbreviated to “bFGF”) play an important role incell proliferation. Among others, bFGF is known to accelerate cellproliferation and migration of vascular endothelial cells, fibloblastsand the like, and is also known to be involved in angiogenesis and woundhealing (Trends. Pharmacol. Sci. April; 22 (4): 201-7, 2001).

Further, the expression of bFGF, or FGFR1 (hereinafter referred to as“Flg”), FGFR2 (hereinafter referred to as “Bek”) and the like belongingto a fibroblast growth factor receptor family is reported to be found invarious cancers such as brain tumors, lung cancer, breast cancer,gastric cancer, head and neck cancer, and prostatic cancer (Proc. Natl.Acad. Sci. USA, 87: 5710-5714, 1990 Oncogene. 1997 August 14; 15 (7):817-26 Cancer Res. 1994 January 15; 54 (2): 523-30. Cancer Res. 1992February 1; 52 (3): 571-7). In particular, it is reported for gastriccancer that overexpression of Bek correlates with poor prognosis mainlyin poorly differentiated cancers such as scirrhus gastric cancers (ClinCancer Res. 1996 August; 2 (8): 1373-81. J Cancer Res Clin Oncol. 2001April; 127 (4): 207-16. Int Rev Cytol. 2001; 204: 49-95.).

There is a plurality of reports on small molecule compounds havinginhibitory activity against the autophosphorylation of Flg (J PharmacolExp Ther. 1998 July; 286 (1): 569-77. Invest New Drugs. 1999; 17 (2):121-35. Cancer Res. 2001 Feb. 15; 61 (4): 1464-8.). On the other hand,there is no report on compounds capable of inhibiting theautophosphorylation of Bek which is considered to be deeply involved inthe progression of gastric cancer.

SUMMARY OF THE INVENTION

The present inventors have found that a certain group of quinolinederivatives and quinazoline derivatives have Bek-autophosphorylationinhibitory activity and, at the same time, have antitumor effect.

An object of the present invention is to provide compounds having potentantitumor activity, more specifically novel compounds which haveinhibitory activity against the autophosphorylation of members of an FGFreceptor family including Bek and, when orally or intraveneouslyadministered, can suppress the growth of cancer cells.

According to the present invention, there is provided a compoundrepresented by formula (I) or a pharmaceutically acceptable salt orsolvate thereof:

wherein

X represents CH or N;

Z represents O or S;

Q represents

—N(—R¹⁰)— wherein R¹⁰ represents a hydrogen atom or C₁₋₄ alkyl,

—C(—R¹¹)(—R¹²)— wherein R¹¹ and R¹², which may be the same or different,represent a hydrogen atom or C₁₋₆ alkylcarbonyloxy,

—C(═O)—,

—O—,

—S(═O)m- wherein m is 0, 1, or 2, or

—NH—C(═O)—NH—;

R¹, R², and R³, which may be the same or different, represent

a hydrogen atom,

hydroxyl,

a halogen atom,

nitro,

amino,

C₁₋₆ alkyl,

C₂₋₆ alkenyl,

C₂₋₆ alkynyl, or

C₁₋₆ alkoxy,

in which the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxygroups, which may be represented by R¹, R², and R³, are optionallysubstituted by hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆alkylcarbonyl; carboxyl; C₁₋₆ alkoxycarbonyl; —(C═O)—NR¹⁴R¹⁵ wherein R¹⁴and R¹⁵, which may be the same or different, represent a hydrogen atomor C₁₋₄ alkyl optionally substituted by hydroxyl, or alternatively R¹⁴and R¹⁵ may combine with the nitrogen atom attached thereto to form asaturated five- or six-membered heterocyclic group; amino in which oneor two hydrogen atoms on the amino group are optionally substituted byC₁₋₆ alkyl or a saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group, and the C₁₋₆ alkyl group isoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;or a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which (i) the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, an oxygen atom, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;(ii) when the carbocyclic or heterocyclic group is substituted by twoC₁₋₆ alkyl groups, the two alkyl groups may combine together to form analkylene chain; and (iii) the carbocyclic or heterocyclic group may becondensed with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic group to form a bicyclic group;

one or two hydrogen atoms on the amino group, which may be representedby R¹, R², and R³, are optionally substituted by C₁₋₆ alkyl which isoptionally substituted by hydroxyl or C₁₋₆ alkoxy;

R⁴ represents a hydrogen atom;

R⁵, R⁶, R⁷, and R⁸, which may be the same or different, represent ahydrogen atom, a halogen atom, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro, or amino;and

R⁹ represents C₁₋₁₀ alkyl or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group in which the three- toeight-membered carbocyclic or heterocyclic group is optionallysubstituted by an oxygen atom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, a halogen atom, or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group, and the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy groups are optionallysubstituted by a halogen atom or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group,

provided that, when Q represents —C(═O)—, R² and R³ do notsimultaneously represent methoxy.

The compounds according to the present invention can be used for thetheraphy and prophylaxis of a disease for which the inhibition ofBek-autophosphorylation is effective therapeutically orprophylactically.

DETAILED DESCRIPTION OF THE INVENTION

Compound

The terms “alkyl,” “alkoxy,” “alkenyl,” and “alkynyl” as used herein asa group or a part of a group respectively mean straight chain orbranched chain alkyl, alkoxy, alkenyl, and alkynyl.

C₁₋₆ alkyl is preferably C₁₋₄ alkyl.

C₁₋₆ alkoxy is preferably C₁₋₄ alkoxy.

C₂₋₆ alkenyl is preferably C₂₋₄ alkenyl.

C₂₋₆ alkynyl is preferably C₂₋₄ alkynyl.

Examples of C₁₋₆ alkyl include methyl, ethyl, n-propyl, isopropyl,n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, and n-hexyl.

Examples of C₁₋₆ alkoxy include methoxy, ethoxy, n-propoxy, i-propoxy,n-butoxy, i-butoxy, s-butoxy, and t-butoxy.

Examples of C₂₋₆ alkenyl include allyl, butenyl, pentenyl, and hexenyl.

Examples of C₂₋₆ alkynyl include 2-propynyl, butynyl, pentynyl, andhexynyl.

The expression “alkyl optionally substituted by” as used herein refersto alkyl, in which one or more hydrogen atoms on the alkyl group havebeen substituted by one or more substituents which may be the same ordifferent, and unsubstituted alkyl. It will be apparent to a personhaving ordinary skill in the art that the maximum number of substituentsmay be determined depending upon the number of substitutable hydrogenatoms on the alkyl group. This is true of a group having a substituentother than the alkyl group.

The term “halogen atom” means a fluorine, chlorine, bromine, or iodineatom.

The saturated or unsaturated three- to eight-membered carbocyclic ringis preferably a four- to seven-membered, more preferably five- orsix-membered, saturated or unsaturated carbocyclic ring. Examples ofsaturated or unsaturated three- to eight-membered carbocyclic ringsinclude phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl.

The saturated or unsaturated three- to eight-membered heterocyclic ringcontains at least one hetero-atom selected from oxygen, nitrogen, andsulfur atoms. The saturated or unsaturated three- to eight-memberedheterocyclic ring preferably contains one, two or three hetero-atomswith the remaining ring-constituting atoms being carbon atoms. Thesaturated or unsaturated three- to eight-membered heterocyclic ring ispreferably a saturated or unsaturated four- to seven-memberedheterocyclic ring, more preferably a saturated or unsaturated five- orsix-membered heterocyclic ring. Examples of saturated or unsaturatedthree- to eight-membered heterocyclic groups include thienyl, pyridyl,1,2,3-triazolyl, thiazolyl, imidazolyl, isoxazolyl, pyrazolyl,piperazinyl, piperazino, piperidyl, piperidino, morpholinyl, morpholino,homopiperazinyl, homopiperazino, thiomorpholinyl, thiomorpholino,tetrahydropyrrolyl, and azepanyl.

The saturated or unsaturated carboxylic and heterocyclic groups maycondense with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic ring to form a bicyclic group, preferably asaturated or unsaturated nine- to twelve-membered bicyclic carbocyclicor heterocyclic group. Such bicyclic groups include naphthyl, quinolyl,1,2,3,4-tetrahydroquinolyl, 1,4-benzoxanyl, indanyl, indolyl,1,2,3,4-tetrahydronaphthyl, and phthalimide.

When the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain, preferably a C₁₋₃ alkylene chain. Carbocyclic orheterocyclic groups having this crosslinked structure includeazabicyclo[2.2.2]octanyl, bicyclo[2.2.2]octanyl and norbornanyl.

R¹ preferably represents a hydrogen atom.

Preferably, R² and R³ may be the same or different and represent a groupother than a hydrogen atom.

More preferably, R² represents unsubstituted C₁₋₆ alkoxy, still morepreferably unsubstituted methoxy, and R³ represents hydroxyl oroptionally substituted C₁₋₆ alkoxy, or alternatively R² representshydroxyl or optionally substituted C₁₋₆ alkoxy and R³ representsunsubstituted C₁₋₆ alkoxy, still more preferably unsubstituted methoxy.

R³, and R¹⁰³ which will be described later preferably represent—O—(CH₂)p-R¹³ wherein p is an integer of 0 to 6, —(CH₂)p- is optionallysubstituted by C₁₋₆ alkyl, hydroxyl, or a halogen atom, and R¹³represents a hydrogen atom; hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆alkylcarbonyl; carboxyl; C₁₋₆ alkoxycarbonyl; —(C═O)—NR¹⁴R¹⁵ wherein R¹⁴and R¹⁵, which may be the same or different, represent a hydrogen atomor C₁₋₄ alkyl optionally substituted by hydroxyl, or alternatively R¹⁴and R¹⁵ may combine with the nitrogen atom attached thereto to form asaturated five- or six-membered heterocyclic group; amino in which oneor two hydrogen atoms on the amino group are optionally substituted byC₁₋₆ alkyl or a saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group, and the C₁₋₆ alkyl group isoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;or a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, an oxygen atom, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;when the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain; and the carbocyclic or heterocyclic group may becondensed with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic group to form a bicyclic group. When p=0,—(CH₂)p- represents a bond.

All of R⁵, R⁶, R⁷, and R⁸ preferably represent a hydrogen atom, or anyone or two of R⁵, R⁶, R⁷, and R⁸ represent a group other than a hydrogenatom with all the remaining groups representing a hydrogen atom.

R⁹ preferably represents a saturated or unsaturated four- toseven-membered carbocyclic or heterocyclic group.

Preferred substituents of the carbocyclic or heterocyclic grouprepresented by R⁹ include an oxygen atom, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄alkoxy, a halogen atom, or a saturated or unsaturated four- toseven-membered carbocyclic or heterocyclic group, and the C₁₋₄ alkyl,C₂₋₄ alkenyl, and C₁₋₄ alkoxy groups are optionally substituted by ahalogen atom or saturated or unsaturated four- to seven-memberedcarbocyclic or heterocyclic group.

R⁹, and R¹⁰⁹ which will be described later preferably represent phenylof which the p-position is substituted by C₁₋₄ alkyl or a saturated orunsaturated four- to seven-membered carbocyclic or heterocyclic group.

R⁹, and R⁴⁰⁹ which will be described later preferably represent C₁₋₄alkyl substituted by t-butyl; or a saturated five- to seven-memberedcarbocyclic group optionally substituted by one, two, or three of C₁₋₄alkyl groups. The C₁₋₄ alkyl substituted by t-butyl preferablyrepresents —(CH₂)t-R⁵¹ wherein t is an integer of 1 to 4 and R⁵¹represents t-butyl.

When Q represents —NH—(C═O)—NH—, R⁹ preferably represents C₁₋₄ alkylsubstituted by t-butyl; or a saturated five- to seven-memberedcarbocyclic group optionally substituted by one, two, or three of C₁₋₄alkyl groups.

Examples of preferred compounds according to the present inventioninclude compounds represented by formula (100):

wherein

X represents CH or N;

Q represents

—N(—R¹¹⁰)— wherein R¹¹⁰ represents a hydrogen atom or C₁₋₄ alkyl,

—C(—R¹¹¹)(—R¹¹²)— wherein R¹¹¹ and R¹¹², which may be the same ordifferent, represent a hydrogen atom or C₁₋₄ alkylcarbonyloxy, or

—O—;

R¹⁰³ represents hydroxyl or C₁₋₆ alkoxy in which the C₁₋₆ alkoxy groupis optionally substituted by hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆alkylcarbonyl; carboxyl; C₁₋₆ alkoxycarbonyl; —(C═O)—NR¹⁴R¹⁵ wherein R¹⁴and R¹⁵, which may be the same or different, represent a hydrogen atomor C₁₋₄ alkyl optionally substituted by hydroxyl, or alternatively R¹⁴and R¹⁵ may combine with the nitrogen atom attached thereto to form asaturated five- or six-membered heterocyclic group; amino in which oneor two hydrogen atoms on the amino group are optionally substituted byC₁₋₆ alkyl or a saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group, and the C₁₋₆ alkyl group isoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;or a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, an oxygen atom, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;when the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain; and the carbocyclic or heterocyclic group may becondensed with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic group to form a bicyclic group;

all of R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸ represent a hydrogen atom, or any oneor two of R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸ represent a halogen atom, C₁₋₄alkyl, C₁₋₄ alkoxy, nitro, or amino with all the remaining groupsrepresenting a hydrogen atom; and

R¹⁰⁹ represents a saturated or unsaturated four- to seven-memberedcarbocyclic or heterocyclic group in which the four- to seven-memberedcarbocyclic or heterocyclic group is optionally substituted by an oxygenatom, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, a halogen atom, or asaturated or unsaturated four- to seven-membered carbocyclic orheterocyclic group, and the C₁₋₄ alkyl, C₂₋₄ alkenyl, and C₁₋₄ alkoxygroups are optionally substituted by a halogen atom or saturated orunsaturated four- to seven-membered carbocyclic or heterocyclic group.

Examples of more preferred compounds according to the present inventioninclude compounds represented by formula (200):

wherein

X represents CH or N;

R²⁰³ represents —O—(CH₂)p-R¹³ wherein p is an integer of 0 to 6,—(CH₂)p- is optionally substituted by C₁₋₆ alkyl, hydroxyl, or a halogenatom, and R¹³ represents a hydrogen atom; hydroxyl; a halogen atom; C₁₋₆alkoxy; C₁₋₆ alkylcarbonyl; carboxyl; C₁₋₆ alkoxycarbonyl;—(C═O)—NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵, which may be the same or different,represent a hydrogen atom or C₁₋₄ alkyl optionally substituted byhydroxyl, or alternatively R¹⁴ and R¹⁵ may combine with the nitrogenatom attached thereto to form a saturated five- or six-memberedheterocyclic group; C₁₋₆ alkoxycarbonyl; amino in which one or twohydrogen atoms on the amino group are optionally substituted by C₁₋₆alkyl or a saturated or unsaturated three- to eight-membered carbocyclicor heterocyclic group, and the C₁₋₆ alkyl group is optionallysubstituted by hydroxyl, C₁₋₆ alkoxy, or a saturated or unsaturatedthree- to eight-membered carbocyclic or heterocyclic group; or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, an oxygen atom, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;when the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain; and the carbocyclic or heterocyclic group may becondensed with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic group to form a bicyclic group;

all of R²⁰⁵, R²⁰⁶, R²⁰⁷, and R²⁰⁸ represent a hydrogen atom, or any oneor two of R²⁰⁵, R²⁰⁶, R²⁰⁷, and R²⁰⁸ represent a halogen atom, C₁₋₄alkyl, C₁₋₄ alkoxy, nitro, or amino with all the remaining groupsrepresenting a hydrogen atom; and

R²⁰⁹ represents C₁₋₄ alkyl or a saturated or unsaturated four- toseven-membered carbocyclic or heterocyclic group and R²¹⁰ represents ahydrogen atom or C₁₋₄ alkyl.

Examples of preferred compounds according to the present inventioninclude compounds represented by formula (300):

wherein

X represents CH or N;

R³⁰² represents —O—(CH₂)p-R¹³ wherein p is an integer of 0 to 6,—(CH₂)p- is optionally substituted by C₁₋₆ alkyl, hydroxyl, or a halogenatom, and R¹³ represents a hydrogen atom; hydroxyl; a halogen atom; C₁₋₆alkoxy; C₁₋₆ alkylcarbonyl; carboxyl; C₁₋₆ alkoxycarbonyl;—(C═O)—NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵, which may be the same or different,represent a hydrogen atom or C₁₋₄ alkyl optionally substituted byhydroxyl, or alternatively R¹⁴ and R¹⁵ may combine with the nitrogenatom attached thereto to form a saturated five- or six-memberedheterocyclic group; C₁₋₆ alkoxycarbonyl; amino in which one or twohydrogen atoms on the amino group are optionally substituted by C₁₋₆alkyl or a saturated or unsaturated three- to eight-membered carbocyclicor heterocyclic group, and the C₁₋₆ alkyl group is optionallysubstituted by hydroxyl, C₁₋₆ alkoxy, or a saturated or unsaturatedthree- to eight-membered carbocyclic or heterocyclic group; or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, an oxygen atom, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;when the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain; and the carbocyclic or heterocyclic group may becondensed with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic group to form a bicyclic group;

all of R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸ represent a hydrogen atom, or any oneor two of R³⁰⁵ R³⁰⁶ R³⁰⁷ and R³⁰⁸ represent a halogen atom, C₁₋₄ alkyl,C₁₋₄ alkoxy, nitro, or amino with all the remaining groups representinga hydrogen atom; and

R³⁰⁹ represents C₁₋₄ alkyl or a saturated or unsaturated four- toseven-membered carbocyclic or heterocyclic group and R³¹⁰ represents ahydrogen atom or C₁₋₄ alkyl.

Examples of preferred compounds according to the present inventioninclude compounds represented by formula (400):

wherein

X represents CH or N;

R⁴⁰² and R⁴⁰³, which may be the same or different, represent—O—(CH₂)p-R¹³ wherein p is an integer of 0 to 6, —(CH₂)p- is optionallysubstituted by C₁₋₆ alkyl, hydroxyl, or a halogen atom, and R¹³represents a hydrogen atom; hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆alkylcarbonyl; carboxyl; C₁₋₆ alkoxycarbonyl; —(C═O)—NR¹⁴R¹⁵ wherein R¹⁴and R¹⁵, which may be the same or different, represent a hydrogen atomor C₁₋₄ alkyl optionally substituted by hydroxyl, or alternatively R¹⁴and R¹⁵ may combine with the nitrogen atom attached thereto to form asaturated five- or six-membered heterocyclic group; C₁₋₆ alkoxycarbonyl;amino in which one or two hydrogen atoms on the amino group areoptionally substituted by C₁₋₆ alkyl or a saturated or unsaturatedthree- to eight-membered carbocyclic or heterocyclic group, and the C₁₋₆alkyl group is optionally substituted by hydroxyl, C₁₋₆ alkoxy, or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group; or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group in which thecarbocyclic or heterocyclic group is optionally substituted by hydroxyl,an oxygen atom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy,C₁₋₆ alkoxycarbonyl, or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group; the C₁₋₆ alkyl, C₂₋₆alkenyl, and C₂₋₆ alkynyl groups are optionally substituted by hydroxyl,C₁₋₆ alkoxy, or a saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group; when the carbocyclic or heterocyclicgroup is substituted by two C₁₋₆ alkyl groups, the two alkyl groups maycombine together to form an alkylene chain; and the carbocyclic orheterocyclic group may be condensed with another saturated orunsaturated five- to seven-membered carbocyclic or heterocyclic group toform a bicyclic group;

all of R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸ represent a hydrogen atom, or any oneor two of R⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸ represent a halogen atom, C₁₋₄alkyl, C₁₋₄ alkoxy, nitro, or amino with all the remaining groupsrepresenting a hydrogen atom; and

R⁴⁰⁹ represents C₁₋₄ alkyl substituted by t-butyl; or a saturated five-to seven-membered carbocyclic group optionally substituted by one, two,or three of C₁₋₄ alkyl groups.

Preferably, any one of R⁴⁰² and R⁴⁰³ represents unsubstituted alkoxy,and the other represents a group other than unsubstituted alkoxy.

Examples of preferred compounds according to the present inventioninclude compounds described in working examples.

Particularly preferred compounds according to the present inventioninclude compounds 37, 59, 70, 71, 79, 81, and 102 described in workingexamples.

The compounds according to the present invention may formpharmaceutically acceptable salts thereof. Preferred examples of suchsalts include: alkali metal or alkaline earth metal salts such as sodiumsalts, potassium salts or calcium salts; hydrohalogenic acid salts suchas hydrofluoride salts, hydrochloride salts, hydrobromide salts, orhydroiodide salts; inorganic acid salts such as nitric acid salts,perchloric acid salts, sulfuric acid salts, or phosphoric acid salts;lower alkylsulfonic acid salts such as methanesulfonic acid salts,trifluoromethanesulfonic acid salts, or ethanesulfonic acid salts;arylsulfonic acid salts such as benzenesulfonic acid salts orp-toluenesulfonic acid salts; organic acid salts such as fumaric acidsalts, succinic acid salts, citric acid salts, tartaric acid salts,oxalic acid salts, maleic acid salts, acetic acid salts, malic acidsalts, lactic acid salts, or ascorbic acid salts; and amino acid saltssuch as glycine salts, phenylalanine salts, glutamic acid salts, oraspartic acid salts.

The compounds according to the present invention may form solvates. Suchsolvates include, for example, hydrates, alcoholates, for example,methanolates and ethanolates, and etherates, for example, diethyletherate.

Production of Compounds

Compounds according to the present invention may be produced, forexample, according to schemes 1 to 14. Starting compounds necessary forthe synthesis of the compounds according to the present invention arecommercially available or alternatively can be easily produced byconventional methods. In the schemes, R¹ to R¹⁰ are as defined informula (I).

For example, a 4-chloroquinoline derivative can be synthesized by aconventional method as described, for example, in Org. Synth. Col. Vol.3, 272 (1955), Acta Chim. Hung., 112, 241 (1983), or WO 98/47873. Scheme1 shows an example of the synthesis of the 4-chloroquinoline derivative.A quinolone derivative is produced by reacting a 2-aminoacetophenonederivative with a formic ester, for example, ethyl formate, in asuitable solvent, for example, tetrahydrofuran, in the presence of abase, for example, sodium methoxide. The 4-chloroquinoline derivative isproduced by reacting the quinolone derivative in the presence of achlorinating agent, for example, phosphorus oxychloride.

For example, a 4-chloroquinazoline derivative can be produced asfollows. A quinazolone derivative is produced by reacting a2-amino-benzoate acid derivative with formamide in a suitable solvent,for example, a mixed solvent composed of N,N-dimethylformamide andmethanol, in the presence of a base, for example, sodium methoxide. The4-chloroquinazoline derivative is produced by reacting the quinazolonederivative in the presence of a chlorinating agent, for example,phosphorus oxychloride.

A 4-(aminophenoxy)quinoline derivative or a corresponding quinazolinederivative is produced by reacting a nitrophenol derivative with the4-chloroquinoline derivative or corresponding quinazoline derivative ina suitable solvent, for example, chlorobenzene, to synthesize a4-(nitrophenoxy)quinoline derivative or a corresponding quinazolinederivative and then reacting the 4-(nitrophenoxy)quinoline derivative orcorresponding quinazoline derivative in a suitable solvent, for example,N,N-dimethyl formamide, in the presence of a catalyst, for example,palladium hydroxide-carbon or palladium-carbon, under a hydrogenatmosphere. The nitro group can also be reduced with zinc, iron or thelike.

Alternatively, the 4-(aminophenoxy)quinoline derivative or correspondingquinazoline derivative can be produced by reacting an aminophenolderivative with the 4-chloroquinoline derivative or correspondingquinazoline derivative in a suitable solvent, for example, dimethylsulfoxide, in the presence of a base, for example, sodium hydride.Alternatively, the 4-(aminophenoxy)quinazoline derivative can also beproduced by dissolving an aminophenol derivative in an aqueous sodiumhydroxide solution and subjecting the solution to a two-phase reactionwith a solution of the 4-chloroquinazoline derivative in a suitableorganic solvent, for example, ethyl methyl ketone, in the presence of aphase transfer catalyst, for example, tetra-n-butylammonium chloride, orin the absence of the catalyst.

The corresponding aniline derivative can be produced by subjecting ananilino group in a 4-(aminophenoxy)quinoline derivative or a quinazolinederivative to arylation under suitable conditions (e.g., mixed solventin the presence of copper(II) acetate) or alkylation under suitableconditions (e.g., condensing the anilino group with a ketone derivativein N,N-dimethylformamide and then reacting the condensate with sodiumborohydride acetate).

A quinoline derivative or a corresponding quinazoline derivative havinga hydroxyl group at its 6- or 7-position can be produced by dissolving a6,7-dimethoxy-4-(nitrophenoxy)quinoline derivative or a correspondingquinazoline derivative in a suitable solvent (for example, chloroform)and heating the solution under reflux in the presence of a suitableLewis acid (for example, aluminum trichloride). A4-(nitrophenoxy)quinoline derivative or corresponding quinazolinederivative containing a specific substituent introduced at its 6- or7-position can be produced by introducing a desired substituent into theintroduced hydroxyl group, or by protecting the hydroxyl group with aprotective group. The hydroxyl group can be protected by reacting anunpurified solid of the derivative with benzyl chloride inN,N-dimethylformamide in the presence of potassium carbonate and thenconducting separation and purification.

A 4-(hydroxyphenoxy)quinoline derivative or a corresponding quinazolinederivative is produced by reacting a phenol derivative with the4-chloroquinoline derivative or corresponding quinazoline derivative ina suitable solvent, for example, chlorobenzene, to synthesize a4-phenoxyquinoline derivative or a corresponding quinazoline derivativeand then removing the protective group of the hydroxyl group undersuitable conditions (for example, when the protective group is benzyl,for example, a reaction is allowed to proceed in N,N-dimethylformamidein the presence of palladium hydroxide-carbon or palladium-carbon in ahydrogen atmosphere). A corresponding ether derivative is produced bysubjecting a hydroxy group in the 4-(hydroxyphenoxy)quinoline derivativeor quinazoline derivative to arylation under suitable conditions (e.g.,reacting the hydroxy group with an aryl borate derivative in achloroform-triethylamine mixed solvent in the presence of copper(II)acetate) or alkylation under suitable conditions (e.g., reacting thehydroxy group with an alkyl halide in N,N-dimethylformamide in thepresence of potassium carbonate.

A corresponding ketone derivative is produced by reacting an acylphenolderivative with a 4-chloroquinoline derivative or a correspondingquinazoline derivative in a suitable solvent (for example,chlorobenzene). A corresponding methylene derivative is produced byreducing the carbonyl group in the ketone derivative under suitableconditions. The acylphenol derivative is commercially available or caneasily be produced by a conventional method. For example, anacyl-containing phenol derivative is produced by reacting a phenolderivative containing a protective hydroxyl group with an acid chloridederivative in a suitable solvent (for example, nitromethane) in thepresence of a Lewis acid (for example, ytterbium(III) triflate), and acorresponding acylphenol derivative is produced by further removing theprotective group of the hydroxyl group under suitable conditions.

For example, an intermediate for synthesizing a derivative having aspecific substituent at the 7-position of the quinoline ring can beproduced according to scheme 5. A nitro group can be introduced byprotecting a commercially available 4′-hydroxyacetophenone derivativewith a suitable substituent, for example, benzyl, and then reacting theprotected 4′-hydroxyacetophenone derivative with a nitrating agent, forexample, fuming nitric acid-acetic acid. The later steps of scheme 5 arecarried out as shown in scheme 1. Specifically, the nitro group isreduced to an amino group which is then reacted with a formic ester inthe presence of a base to give a quinolone ring. Next, the quinolonering is reacted with a chlorinating agent to give a 4-chloroquinolinederivative. In the chlorination reaction, when phosphorus oxychloride isused as the chlorinating agent, the yield can be improved by adding abase, for example, N,N-diisopropylethylamine.

An intermediate for synthesizing a derivative having a specificsubstituent at the 6-position of the quinoline ring can be produced byusing a 3′-hydroxyacetophenone derivative instead of the4′-hydroxyacetophenone derivative.

For example, an intermediate for synthesizing a derivative having aspecific substituent at the 7-position of the quinazoline ring can beproduced according to scheme 6. A nitro group can be introduced byprotecting a hydroxyl group in a commercially available 4′-hydroxybezoicester derivative with a suitable substituent, for example, benzyl, andthen reacting the product with a nitrating agent, for example, fumingnitric acid-acetic acid. The later steps of scheme 6 are carried out asshown in scheme 1. Specifically, a quinazolone ring is formed byreducing the nitro group to an amino group and then reacting the productwith formamide in the presence of a base. Next, a 4-chloroquinazolinederivative can be produced by reacting the product with a chlorinatingagent. In the chlorination reaction, when phosphorus oxychloride is usedas a chlorinating agent, the addition of a base, for example,N,N-diisopropylethylamine can improve the yield.

An intermediate for synthesizing a derivative having a specificsubstituent at the 6-position of the quinazoline ring can be produced byusing a 3′-hydroxybenozic ester derivative instead of the4′-hydroxybenzoic ester derivative.

An aniline derivative having a specific substituent at the 7-position ofthe quinoline or quinazoline ring can be produced, for example,according to scheme 7. Specifically, a 4-(aminophenoxy)quinolinederivative or a corresponding quinazoline derivative is produced byreacting the 4-chloroquinoline derivative or quinazoline derivativeproduced in scheme 5 or scheme 6 with a nitrophenol derivative in asuitable solvent, for example, chlorobenzene, to synthesize a4-(nitrophenoxy)quinoline derivative or a corresponding quinazolinederivative and then reacting the 4-(nitrophenoxy)quinoline derivative orcorresponding quinazoline derivative in a suitable solvent, for example,N,N-dimethyl formamide, in the presence of a catalyst, for example,palladium hydroxide-carbon or palladium-carbon, under a hydrogenatmosphere. The nitro group can also be reduced with zinc, iron or thelike. Alternatively, the 4-(aminophenoxy)quinoline derivative orcorresponding quinazoline derivative may be produced by reacting anaminophenol derivative with the 4-chloroquinoline derivative orcorresponding quinazoline derivative in a suitable solvent, for example,dimethyl sulfoxide, in the presence of a base, for example, sodiumhydride. Alternatively, the 4-(aminophenoxy)quinazoline derivative mayalso be produced by dissolving an aminophenol derivative in an aqueoussodium hydroxide solution and subjecting the solution to a two-phasereaction with a solution of the 4-chloroquinazoline derivative in asuitable organic solvent, for example, ethyl methyl ketone, in thepresence of a phase transfer catalyst, for example,tetra-n-butylammonium chloride, or in the absence of the catalyst. Acorresponding aniline derivative, in which the hydroxyl group at the7-position of quinoline or quinazoline has been protected, is producedby subjecting an anilino group in a 4-(aminophenoxy)quinoline derivativeor a quinazoline derivative to arylation under suitable conditions(e.g., reacting the anilino group with an aryl borate derivative in achloroform-triethylamine mixed solvent in the presence of copper(II)acetate) or alkylation under suitable conditions (e.g., condensing theanilino group with a ketone derivative in N,N-dimethylformamide and thenreacting the condensate with sodium borohydride acetate). A7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazolinederivative is produced by removing the protective group of the hydroxylgroup in the aniline derivative under suitable conditions (for example,when the protective group is benzyl, for example, a reaction is allowedto proceed in N,N-dimethylformamide in the presence of palladiumhydroxide-carbon or palladium-carbon in a hydrogen atmosphere). Next, ananiline derivative having a specific substituent at the 7-position ofthe quinoline or quinazoline ring is produced by alkylating the7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazolinederivative under suitable conditions (e.g., reacting the derivative withan alkyl halide in N,N-dimethylformamide in the presence of potassiumcarbonate).

A method for synthesizing the compound according to the presentinvention having a substituent at the 7-position of the quinoline ringor the quinazoline ring is disclosed in scheme 7. When a quinolinederivative or quinazoline derivative containing a protective groupintroduced into its 6-position is used as a starting compound, thecompound according to the present invention having a substituent at the6-position of the quinoline ring or quinazoline ring can be synthesized.The quinoline derivative or quinazoline derivative containing aprotective group introduced at the 6-position to be used as the startingcompound can be synthesized, for example, according to scheme 18 whichwill be described later.

An ether derivative having a specific substituent at the 7-position ofthe quinoline ring or quinazoline ring can be produced, for example,according to scheme 8. Specifically, a 4-(hydroxyphenoxy)quinolinederivative or a corresponding quinazoline derivative is produced byreacting a phenol derivative with the 4-chloroquinoline derivative orquinazoline derivative produced in scheme 5 or 6 in a suitable solvent,for example, chlorobenzene, to synthesize a 4-phenoxyquinolinederivative or a corresponding quinazoline derivative and then removingthe protective group of the hydroxyl group under suitable conditions(for example, when the protective group is benzyl, for example, areaction is allowed to proceed in N,N-dimethylformamide in the presenceof palladium hydroxide-carbon or palladium-carbon in a hydrogenatmosphere). A corresponding ether derivative having a protectedhydroxyl group at the 7-position of quinoline or quinazoline is produedby subjecting a hydroxy group in the 4-(hydroxyphenoxy)quinolinederivative or quinazoline derivative to arylation under suitableconditions (e.g., reacting the hydroxy group with an aryl boratederivative in a chloroform-triethylamine mixed solvent in the presenceof copper(II) acetate) or alkylation under suitable conditions (e.g.,reacting the hydroxy group with an alkyl halide in N,N-dimethylformamidein the presence of potassium carbonate). A 7-hydroxyquinoline derivativeor a corresponding 7-hydroxyquinazoline derivative is produced byremoving the protective group of the hydroxyl group in the etherderivative under suitable conditions (for example, when the protectivegroup is benzyl, for example, a reaction is allowed to proceed inN,N-dimethylformamide in the presence of palladium hydroxide-carbon orpalladium-carbon in a hydrogen atmosphere). Next, an ether derivativehaving a specific substituent at the 7-position of the quinoline orquinazoline ring is produced by alkylating the 7-hydroxyquinolinederivative or corresponding 7-hydroxyquinazoline derivative undersuitable conditions (e.g., reacting the derivative with an alkyl halidein N,N-dimethylformamide in the presence of potassium carbonate).

A method for synthesizing the compound according to the presentinvention having a substituent at the 7-position of the quinoline ringor the quinazoline ring is disclosed in scheme 8. When a quinolinederivative or quinazoline derivative containing a protective groupintroduced into its 6-position is used as a starting compound, thecompound according to the present invention having a substituent at the6-position of the quinoline ring or quinazoline ring can be synthesized.The quinoline derivative or quinazoline derivative containing aprotective group introduced at the 6-position to be used as the startingcompound can be synthesized, for example, according to scheme 18 whichwill be described later.

A ketone derivative having a specific substituent at the 7-position ofthe quinoline or quinazoline ring can be produced, for example,according to scheme 9. Specifically, a ketone derivative having aprotected hydroxyl group at the 7-position of quinoline or quinazolineis produced by reacting the 4-chloroquinoline derivative or quinazolinederivative produced in scheme 5 or scheme 6 with an acylphenolderivative in a suitable solvent, for example, chlorobenzene. A7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazolinederivative is produced by removing the protective group of the hydroxylgroup in the ketone derivative under suitable conditions (for example,when the protective group is benzyl, for example, a reaction is allowedto proceed in N,N-dimethylformamide in the presence of palladiumhydroxide-carbon or palladium-carbon in a hydrogen atmosphere). Next, aketone derivative having a specific substituent at the 7-position of thequinoline or quinazoline ring is produced by alkylating the7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazolinederivative under suitable conditions (e.g., reacting the derivative withan alkyl halide in N,N-dimethylformamide in the presence of potassiumcarbonate).

A method for synthesizing the compound according to the presentinvention having a substituent at the 7-position of the quinoline ringor the quinazoline ring is disclosed in scheme 9. When a quinolinederivative or quinazoline derivative containing a protective groupintroduced into its 6-position is used as a starting compound, thecompound according to the present invention having a substituent at the6-position of the quinoline ring or quinazoline ring can be synthesized.The quinoline derivative or quinazoline derivative containing aprotective group introduced at the 6-position to be used as the startingcompound can be synthesized, for example, according to scheme 18 whichwill be described later.

A methylene derivative having a specific substituent at the 7-positionof the quinoline or quinazoline ring can be produced, for example,according to scheme 10. Specifically, a corresponding methylenederivative is produced by reducing the carbonyl group of the ketonederivative having a protected hydroxyl group at the 7-position ofquinoline or quinazoline produced in scheme 9 under suitable conditions.A 7-hydroxyquinoline derivative or a corresponding 7-hydroxyquinazolinederivative is produced by removing the protective group of the hydroxylgroup in the methylene derivative under suitable conditions (forexample, when the protective group is benzyl, for example, a reaction isallowed to proceed in N,N-dimethylformamide in the presence of palladiumhydroxide-carbon or palladium-carbon in a hydrogen atmosphere). Next, amethylene derivative having a specific substituent at the 7-position ofthe quinoline or quinazoline ring is produced by alkylating the7-hydroxyquinoline derivative or corresponding 7-hydroxyquinazolinederivative under suitable conditions (e.g., reacting the derivative withan alkyl halide in N,N-dimethylformamide in the presence of potassiumcarbonate).

A method for synthesizing the compound according to the presentinvention having a substituent at the 7-position of the quinoline ringor the quinazoline ring is disclosed in scheme 10. When a quinolinederivative or quinazoline derivative containing a protective groupintroduced into its 6-position is used as a starting compound, thecompound according to the present invention having a substituent at the6-position of the quinoline ring or quinazoline ring can be synthesized.The quinoline derivative or quinazoline derivative containing aprotective group introduced at the 6-position to be used as the startingcompound can be synthesized, for example, according to scheme 18 whichwill be described later.

A 4-(quinolylsulfanyl)aniline derivative or a4-(quinazolinylsulfanyl)aniline derivative (a compound represented byformula (I) in which Z represents S) is produced by reacting anaminothiophenol derivative with a 4-chloroquinoline derivative or acorresponding quinazoline derivative in a suitable solvent, for example,chlorobenzene.

A compound represented by formula (I), wherein Q represents S, isproduced by reacting a phenol derivative with a 4-chloroquinolinederivative or a corresponding quinazoline derivative in a suitablesolvent, for example, chlorobenzene, to synthesize a 4-phenoxyquinolinederivative or a corresponding quinazoline derivative and then reactingthe 4-phenoxyquinoline derivative or corresponding quinazolinederivative with NaS—R⁹ in a suitable solvent, for example, ethyleneglycol, in the presence of a catalyst, for example, a nickel catalyst.

An ester derivative (a compound represented by formula (I) wherein R¹¹or R¹² represents C₁₋₆ alkylcarbonyloxy) is produced, for example, byallowing sodium borohydride to act in ethanol to give an alcoholderivative and then reacting the alcohol derivative with an acylatingagent, for example, acetic anhydrie, in a suitable solvent, for example,N,N-dimethylformamide in the presence of a base, for example,triethylamine.

A urea derivative having a specific substituent at the 6- or 7-positionof the quinoline or quinazoline ring can be produced, for example,according to scheme 14. Specifically, a urea derivative having aprotected hydroxyl group at the 7-position of quinoline or quinazolinecan be produced by dissolving the 4-(aminophenoxy)quinoline derivativeor corresponding quinazoline derivative produced in scheme 7 in asuitable solvent, for example, chloroform to prepare a solution, addingtriphosgene or a chloroformic ester to the solution in the presence of asuitable base, for example, triethylamine, and reacting the mixture witha suitable alkylamine. A 7-hydroxyquinoline derivative or acorresponding quinazoline derivative can be produced by deprotecting thehydroxyl group of the urea derivative under suitable conditions. Forexample, when the protective group is benzyl, the urea derivative isreacted in a hydrogen atmosphere in N,N-dimethylformamide in thepresence of palladium hydroxide-carbon or palladium-carbon. Next, a ureaderivative having a specific substituent at the 7-position of quinolineor quinazoline can be produced by alkylating the 7-hydroxyquinolinederivative or corresponding quinazoline derivative under suitableconditions (for example, reacting the 7-hydroxyquinoline derivative orcorresponding quinazoline derivative with an alkyl halide (RHal) inN,N-dimethylformamide in the presence of potassium carbonate, orreacting the 7-hydroxyquinoline derivative or corresponding quinazolinederivative with an alkyl alcohol (ROH) by a Mitsunobu reaction).

A quinoline derivative or corresponding quinazoline derivative having ahydroxyl group at the 6- or 7-position of quinoline or quinazoline canbe produced by dissolving a 6,7-dimethoxy-4-(nitrophenoxy)quinolinederivative or corresponding quinazoline derivative having a specificsubstituent at the 6- or 7-position of the quinoline ring or quinazolinering in a suitable solvent, for example, chloroform, to prepare asolution and heating the solution under reflux in the presence of asuitable Lewis acid, for example, aluminum trichloride. A4-(nitrophenoxy)quinoline derivative or corresponding quinazolinederivative having a protective group at its 6- or 7-position can beproduced by protecting the hydroxyl group of this derivative undersuitable conditions and then conducting separation and purification. Thehydroxyl group may be protected, for example, with a benzyl group, andthe benzyl group can be introduced by reacting the derivative withbenzyl chloride in N,N-dimethylformamide in the presence of potassiumcarbonate. A 4-(aminophenoxy)quinoline derivative or a correspondingquinazoline derivative can be derived from the derivative thus obtainedin the same manner as in scheme 7. A urea derivative having a specificsubstituent at the 6- or 7-position of the quinoline ring or quinazolinering can be produced from this derivative according to scheme 14.

A method for synthesizing the compound according to the presentinvention having a substituent at the 7-position of the quinoline ringor the quinazoline ring is disclosed in scheme 14. When a quinolinederivative or quinazoline derivative containing a protective groupintroduced into its 6-position is used as a starting compound, thecompound according to the present invention having a substituent at the6-position of the quinoline ring or quinazoline ring can be synthesized.The quinoline derivative or quinazoline derivative containing aprotective group introduced at the 6-position to be used as the startingcompound can be synthesized, for example, according to scheme 18, whichwill be described later, and scheme 7.

A urea derivative having a specific substituent at the 7-position of thequinoline ring or at the 7-position of the quinazoline ring can also besynthesized according to the method described in WO 00/43366.

Use of Compounds/Pharmaceutical Composition

Overexpression of Bek, overexpression of Bek variants and the like inpoorly differentiated gastric cancers, mainly scirrhus gastric cancers,are reported, and Bek signals are considered to be involved inmalignancy of cancer cells (Biochem. Biophys. Res. Commun. 265, 739-745,1999, Surg Oncol. 2000 July; 9 (1): 5-11.). Further, as with VEGF, bFGFis reported to accelerate angiogenesis (Am J Surg. 1997 November; 174(5): 540-4. Arterioscler Thromb Vasc Biol. 2000 May; 20 (5): 1250-6.)and is considered to be involved in angiogenesis in cancers. Therefore,the growth of cancer cells and angiogenesis can be suppressed byinhibiting the autophosphorylation of Bek.

The compounds according to the present invention inhibited in vitro theBek-autophosphorylation which constitutively occurs in human gastriccancer cells (OCUM-2MD3) bFGF-independently (see Pharmacological TestExample 1).

Further, the compounds according to the present invention actuallyexhibited in vivo tumor growth inhibitory activity against human gastriccancer cells (OCUM-2MD3) (see Pharmacological Test Examples 2 and 3).

Accordingly, the compounds according to the present invention are usefulfor the treatment or prophylaxis of a disease for which the inhibitionof Bek-autophosphorylation is effective therapeutically orprophylactically.

Diseases for which the inhibition of Bek-autophosphorylation iseffective therapeutically or prophylactically include malignant tumorssuch as brain tumors, colon cancer, pancreatic cancer, lung cancer,renal cancer, ovarian cancer, and prostatic cancer, preferably solidtumors.

According to the present invention, there is provided a pharmaceuticalcomposition comprising the compound according to the present invention.The pharmaceutical composition according to the present invention can beused for the treatment or prophylaxis of diseases for which theinhibition of Bek-autophosphorylation is effective therapeutically orprophylactically.

Further, according to the present invention, there is provided a methodfor treating or preventing a disease for which the inhibition ofBek-autophosphorylation is effective therapeutically orprophylactically, said method comprising the step of administering atherapeutically or prophylactically effective amount of the compoundaccording to the present invention together with a pharmaceuticallyacceptable carrier to a mammal.

According to the present invention, there is provided use of thecompound according to the present invention, for the manufacture of anagent for use in the treatment or prophylaxis of a disease for which theinhibition of Bek-autophosphorylation is effective therapeutically orprophylactically.

The compounds according to the present invention can be administered tohuman and non-human animals orally or parenterally by administrationroutes, for example, intravenous administration, intramuscularadministration, subcutaneous administration, rectal administration, orpercutaneous administration. Therefore, the pharmaceutical compositioncomprising as an active ingredient the compound according to the presentinvention is formulated into suitable dosage forms according to theadministration routes.

Specifically, oral preparations include tablets, capsules, powders,granules, and syrups, and parental preparations include injections,suppositories, tapes, and ointments.

These various preparations may be prepared by conventional methods, forexample, with commonly used excipients, disintegrants, binders,lubricants, colorants, and diluents.

Excipients include, for example, lactose, glucose, corn starch, sorbit,and crystalline cellulose. Disintegrants include, for example, starch,sodium alginate, gelatin powder, calcium carbonate, calcium citrate, anddextrin. Binders include, for example, dimethylcellulose, polyvinylalcohol, polyvinyl ether, methylcellulose, ethylcellulose, gum arabic,gelatin, hydroxypropylcellulose, and polyvinyl pyrrolidone. Lubricantsinclude, for example, talc, magnesium stearate, polyethylene glycol, andhydrogenated vegetable oils.

In preparing the injections, if necessary, for example, buffers, pHadjustors, stabilizers, tonicity agents, and preservatives may be added.

The content of the compound according to the present invention in thepharmaceutical composition according to the present invention may varydepending upon the dosage form. In general, however, the content is 0.5to 50% by weight, preferably 1 to 20% by weight, based on the wholecomposition.

The dose may be appropriately determined in consideration of, forexample, the age, weight, sex, difference in diseases, and severity ofcondition of individual patients, preferably in the range of 1 to 100mg/kg. This dose is administered at a time daily or divided doses ofseveral times daily.

The compound according to the present invention may be administered incombination with other medicament, for example, a carcinostatic agent.In this case, the compound according to the present invention may beadministered simultaneously with or after or before the administrationof other medicament. The type, administration intervals and the like ofthe carcinostatic agent may be determined depending upon the type ofcancer and the condition of patients.

EXAMPLES

The present invention is further illustrated by the following Examplesthat are not intended as a limitation of the invention.

Necessary starting compounds were produced as described in WO 97/17329,WO 98/47873, WO 00/43366, and Japanese Patent Laid-Open No. 328782/1997.Starting compounds not described in these publications were produced asdescribed in Preparation Examples below.

Preparation Example 1 (Starting Compound 1)

4-Aminophenol (12.21 g) and sodium methoxide (28% methanol solution,21.07 g) were dissolved in N,N-dimethylacetamide (140 ml) to prepare asolution which was then stirred at room temperature for one hr. Thesolvent was removed by evaporation under the reduced pressure.7-(Benzyloxy)-4-chloro-6-methoxyquinoline (21.00 g) andN,N-dimethylacetamide (210 ml) were added to the residue, and themixture was stirred at 120° C. for 22 hr. The solvent was removed byevaporation under the reduced pressure. Water (300 ml) was added to theresidue, and the mixture was stirred at room temperature for 4 hr. Theresultant precipitate was collected by filtration and was dried to givethe target compound (24.90 g, yield 96%).

Preparation Example 2 (Starting Compound 2)

4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}aniline (18.60 g),4-tert-butylphenylboronic acid (17.8 g), copper(II) acetate (22.7 g),and triethylamine (50 ml) were added to chloroform, and the mixture wasstirred at room temperature for 96 hr. Water was added to the reactionsolution, and the mixture was extracted with chloroform. The chloroformlayer was dried over sodium sulfate. The solvent was removed byevaporation under the reduced pressure. The crude was purified bychromatography on silica gel using chloroform/acetone for development togive the target compound (7.89 g, yield 31%).

Preparation Example 3 (Starting Compound 3)

7-(Benzyloxy)-4-chloro-6-methoxyquinoline (9.00 g) and3-fluoro-4-nitrophenol (5.66 g) were added to chlorobenzene (60 ml), andthe mixture was stirred at 120° C. for 21 hr. Chloroform (100 ml) and anaqueous sodium hydroxide solution (prepared by dissolving sodiumhydroxide (2.4 g) in water (100 ml)) were added to the reactionsolution, and the mixture was stirred at room temperature overnight. Theorganic layer was extracted with chloroform, and the chloroform layerwas washed with an aqueous saturated sodium hydrogencarbonate solutionand saturated brine. The chloroform layer was dried over sodium sulfate.The solvent was removed by evaporation under the reduced pressure. Thecrude thus obtained was washed with hexane/ethyl acetate (1/1), then thetarget compound was collected by filtration, dried and given (10.39 g,yield 82%).

Preparation Example 4 (Starting Compound 4)

7-(Benzyloxy)-4-(3-fluoro-4-nitrophenoxy)-6-methoxyquinoline (4.11 g),ammonium chloride (2.62 g), and zinc (12.80 g) were added to methanol(80 ml), and the mixture was stirred at 100° C. for 3 hr. The reactionsolution was filtered, and the filtrate was concentrated. An aqueoussaturated sodium hydrogencarbonate solution was added to the crude thusobtained, and the mixture was stirred at room temperature overnight.Chloroform was added to the solution, and the mixture was extracted. Thechloroform layer was dried over sodium sulfate. The solvent was removedby evaporation under the reduced pressure to give the target compound(1.80 g, yield 47%).

Preparation Example 5 (Starting Compound 5)

4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-fluoroaniline (1.78 g),4-tert-butylphenylboronic acid (1.62 g), copper(II) acetate (2.07 g),and triethylamine (6 ml) were added to chloroform (100 ml), and themixture was stirred at room temperature overnight. Further,4-tert-butylboronic acid (0.81 g) and copper(II) acetate (1.03 g) wereadded thereto, and the mixture was stirred at room temperatureovernight. Water was added to the reaction solution, and the mixture wasextracted with chloroform. The chloroform layer was dried over sodiumsulfate. The solvent was removed by evaporation under the reducedpressure to give a crude which was then purified by chromatography onsilica gel using chloroform/acetone for development to give the targetcompound (1.94 g, yield 82%).

Preparation Example 6 (Starting Compound 6)

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinolyl]oxy}-2-fluorophenyl)-N-[4-(tert-butyl)phenyl]amine(1.94 g) and methanesulfonic acid (1 ml) were added to trifluoroaceticacid (20 ml), and the mixture was heated under reflux for one hr. Thesolvent in the reaction solution was removed by evaporation under thereduced pressure. An aqueous saturated sodium hydrogencarbonate solutionwas added to the crude thus obtained, and the mixture was extracted withchloroform. The chloroform layer was dried over anhydrous sodiumsulfate, and the solvent was removed by evaporation under the reducedpressure to give a crude which was then purified by chromatography onsilica gel using chloroform/methanol for development to give the targetcompound (1.28 g, yield 80%).

Preparation Example 7 (Starting Compound 7)

6,7-Dimethoxy-4-chloroquinoline (4.00 g) and 4-benzyloxyphenol (7.15 g)were added to chlorobenzene (4 ml), and the mixture was heated underreflux overnight. Chloroform and an aqueous sodium hydroxide solutionwere added to the reaction solution, and the mixture was stirred at roomtemperature. The organic layer was extracted with chloroform, and thechloroform layer was washed with an aqueous saturated sodiumhydrogencarbonate solution. The chloroform layer was then dried oversodium sulfate. The solvent was removed by evaporation under the reducedpressure to give a crude which was then purified by chromatography onsilica gel using hexane/acetone/dichloromethane for development to givethe target compound (4.04 g, yield 58%).

Preparation Example 8 (Starting Compound 8)

4-[4-(Benzyloxy)phenoxy]-6,7-dimethoxyquinoline (3.00 g) and palladiumhydroxide (600 mg) were added to N,N-dimethylformamide (150 ml), and themixture was stirred in a hydrogen atmosphere at 60° C. overnight. Thereaction solution was filtered through Celite. The solvent was removedby evaporation under the reduced pressure. The crude thus obtained waswashed with methanol, followed by filtration and drying toquantitatively give the target compound.

Preparation Example 9 (Starting Compound 9)

7-(Benzyloxy)-4-chloro-6-methoxyquinazoline (500 mg) andtetra-n-butylammonium chloride (230 mg) were added to ethyl methylketone (20 ml) (solution A). 4-Aminophenol (270 mg) and sodium hydroxide(99 mg) were added to water (10 ml) (solution B). Solution A andsolution B were mixed together, and the mixture was heated under refluxfor 2 hr. Ethyl methyl ketone was removed by evaporation under thereduced pressure, and the crude was extracted with chloroform. Thechloroform layer was washed with an aqueous saturated sodium carbonatesolution and saturated brine and was then dried over anhydrous sodiumsulfate. The solvent was removed by evaporation under the reducedpressure to give a crude which was then purified by chromatography onsilica gel using chloroform/acetone for development to quantitativelygive the target compound.

Preparation Example 10 (Starting Compound 10)

4-{[7-(Benzyloxy)-6-methoxy-4-quinazolinyl]oxy}aniline (620 mg),4-tert-butylphenylboronic acid (530 mg), copper(II) acetate (660 mg),and triethylamine (2 ml) were added to chloroform (30 ml), and themixture was stirred at room temperature overnight. Water was added tothe reaction solution, and the mixture was extracted with chloroform.The chloroform layer was dried over sodium sulfate. The solvent wasremoved by evaporation under the reduced pressure to give a crude whichwas purified by chromatography on silica gel using chloroform/acetonefor development to give the target compound (0.45 g, yield 54%).

Preparation Example 11 (Starting Compound 11)

N-(4-{[7-(Benzyloxy)-6-methoxy-4-quinazolinyl]oxy}phenyl)-N-[4-(tert-butyl)phenyl]amine(0.45 g) and methanesulfonic acid (0.5 ml) were added to trifluoroaceticacid (10 ml), and the mixture was heated under reflux for one hr. Thesolvent in the reaction solution was removed by evaporation under thereduced pressure. An aqueous saturated sodium hydrogencarbonate solutionwas added to the crude thus obtained, and the mixture was extracted withchloroform. The chloroform layer was dried over anhydrous sodiumsulfate, and the solvent was removed by evaporation under the reducedpressure to give a crude which was then purified by chromatography onsilica gel using chloroform/acetone for development to give the targetcompound (0.20 g, yield 54%).

Preparation Example 12 Production of2-amino-5-benzyloxy-4-methoxyacetophenone (Starting Compound 16)

3′,4′-Dihydroxyacetophenone (20.1 g) was dissolved inN,N-dimethylformamide (320 ml) to prepare a solution. Lithium carbonate(24.4 g) and methyl iodide (20.5 ml) were added to the solution, and themixture was stirred at 55° C. overnight. The reaction solution wasice-cooled and was acidified by the addition of a 10% aqueoushydrochloric acid solution. Chloroform was added to the solution, andthe mixture was extracted twice. The extract was washed with saturatedbrine, was dried over sodium sulfate, and was then evaporated todryness. The solid was dissolved in N,N-dimethylformamide (200 ml).Potassium carbonate (21.8 g), tetrabutylammonium iodide (4.8 g), andbenzyl bromide (18.9 ml) were added to the solution, and the mixture wasstirred at 100° C. for one hr. Water was added thereto, and the mixturewas extracted twice with chloroform. The extract was washed withsaturated brine, was dried over sodium sulfate, and was then evaporatedto dryness. The solid was dissolved in acetic acid (95 ml). Fumingnitric acid (13.6 ml) was added to the solution by portions under icecooling, and the mixture was stirred at room temperature for 3 hr. Underice cooling, the mixture was neutralized by the addition of a 10%aqueous sodium hydroxide solution. Chloroform was added thereto todissolve the resultant solid. The reaction solution was extracted twicewith chloroform. The extract was washed with saturated brine, was driedover sodium sulfate, and was then evaporated to dryness. Ethanol wasadded to the solid, and the mixture was heated to 100° C. to dissolvethe solid in ethanol. Water (20 ml), ammonium chloride (21.1 g), andzinc powder (112 g) were added to the solution, and the mixture wasstirred at 100° C. for one hr. The reaction solution was filtered whilehot, and the filtrate was washed with a chloroform-methanol mixedsolution. The mother liquor was concentrated. Ethyl acetate and 10%sodium hydroxide were added to the residue, the mixture was vigorouslystirred, and the insolubles were then removed by filtration. The motherliquor was extracted with ethyl acetate, and the extract was washed withsaturated brine, was dried over sodium sulfate, and was then evaporatedto dryness. The solid thus obtained was purified by chromatography onsilica gel using hexane/ethyl acetate/dichloromethane for development togive the title compound (13.1 g, yield 37%) (4 steps).

¹H-NMR (CDCl₃, 400 MHz): 2.39 (s, 3H), 3.89 (s, 3H), 5.05 (s, 2H), 6.25(s, 1H), 7.15 (s, 1H), 7.29-7.45 (m, 5H)

Preparation Example 13 Production of 6-benzyloxy-7-methoxy-4-quinolone(Starting Compound 17)

2-Amino-5-benzyloxy-4-methoxyacetophenone (13.1 g), tetrahydrofuran(anhydrous) (200 ml), and sodium methoxide (5 eq, 13.1 g) were added,and the mixture was stirred at room temperature for 30 min. Ethylformate (5 eq, 19.4 ml) was added thereto, and the mixture was furtherstirred at room temperature for one hr. Water was added thereto, and themixture was stirred at room temperature for one hr, followed byconcentration under the reduced pressure. The concentrate was renderedweakly acidic by the addition of 10% aqueous hydrochloric acid.Chloroform was added thereto, the mixture was extracted with chloroform,and the extract was washed with saturated brine, was dried over sodiumsulfate, and the solvent was then removed by evaporation under thereduced pressure. The crude thus obtained was purified by chromatographyon silica gel using chloroform/methanol for development to give thetitle compound (11.5 g, yield 85%).

¹H-NMR (CDCl₃, 400 MHz): δ 3.97 (s, 3H), 5.19 (s, 2H), 6.28 (d, J=7.3Hz, 1H), 7.02 (s, 1H), 7.29-7.41 (m, 3H), 7.47-7.51 (m, 2H), 7.71 (s,1H), 7.86 (d, J=7.3 Hz, 1H)

Preparation Example 14 Production of6-benzyloxy-4-chloro-7-methoxy-quinoline (Starting Compound 18)

6-Benzyloxy-7-methoxy-4-quinolone (2.4 g), diisopropylamine (5 eq, 7.4ml), and phosphorus oxychloride (2.5 eq, 2.0 ml) were added, and themixture was stirred at 110° C. for one hr. The stirred mixture wasconcentrated under the reduced pressure. Chloroform and iced water werethen added to the concentrate. The mixture was rendered weakly alkalineby the addition of 28% aqueous ammonia, followed by extraction withchloroform. The extract was washed with saturated brine and was driedover sodium sulfate, and the solvent was then removed by evaporationunder the reduced pressure. The crude thus obtained was purified bychromatography on silica gel using chloroform/methanol for developmentto give the title compound (1.6 g, yield 63%).

¹H-NMR (CDCl₃, 400 MHz): δ 4.04 (s, 3H), 5.32 (s, 2H), 7.32-7.44 (m,4H), 7.45 (s, 1H), 7.49 (s, 1H), 7.51-7.55 (m, 2H), 8.57 (d, J=4.9 Hz,1H) Mass spectrometric value (ESI-MS, m/z): 300 (M+1)

Preparation Example 15 Production of4-[(6-benzyloxy-7-methoxy-4-quinolyl)oxy]-3-fluoro-nitrobenzene(Starting Compound 19)

4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoro-nitrobenzene (4.3 g) wasdissolved in chloroform (200 ml) to prepare a solution. Aluminiumchloride (10 g) was added to the solution, and the mixture was heatedunder reflux for 2 hr. The solvent was removed by evaporation beforewater (200 ml) was carefully added to the residue. The precipitatedcrude crystal (6.5 g) was collected by filtration. This crude crystalwas dissolved in dimethylformamide (150 ml). Potassium carbonate (9.0 g)and benzyl chloride (4.5 g) were added to the solution, and the mixturewas stirred at room temperature for 5 hr. The mixture was extracted withethyl acetate. The extract was then washed with saturated brine and wasdried over anhydrous sodium sulfate, and the solvent was removed byevaporation under the reduced pressure. The residue was purified bycolumn chromatography on silica gel, and the title compound (1.4 g,yield 27%) was obtained from the fraction of n-hexane:ethyl acetate(1:4).

¹H-NMR (CDCl₃, 400 MHz): 4.04 (s, 3H), 5.26 (s, 2H), 6.57 (d, J=5.1 Hz,1H), 7.15-7.47 (m, 6H), 7.33 (s, 1H), 7.47 (s, 1H), 8.02-8.05 (m, 1H),8.13-8.16 (m, 1H), 8.57 (d, J=5.1 Hz, 1H)

Compound 5:(4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amine

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (689 mg) (starting compound A)and 4-t-butylphenylboronic acid (450 mg) (starting compound B) weredissolved in a mixed solution composed of dichloromethane (50 ml) andtriethylamine (0.7 ml) to prepare a solution. Copper(II) acetate (450mg) was added to the solution, and the mixture was stirred at roomtemperature for 16 hr. The mixture was filtered, and the filtrate wasthen concentrated to give a crude which was then purified bychromatography on silica gel to give the title compound (500 mg, yield50%).

¹H-NMR (CDCl₃, 400 MHz): 1.24 (s, 9H), 4.13 (s, 3H), 4.15 (s, 3H), 5.75(brs, 1H), 6.41 (d, J=5.4 Hz, 1H), 6.96-7.06 (m, 6H), 7.22 -7.26 (m,2H), 7.34 (s, 1H), 7.51 (s, 1H), 8.40 (d, J=5.1 Hz, 1H) Massspectrometric value (m/z): 429 [M+H]⁺

Compound 20:(4-Tert-butylphenyl)-[4-(6.7-dimethoxyuinolin-4-yloxy)phenyl]-methylamine

[4-(6,7-Dimethoxy-4-quinolyloxy)phenyl]methylamine (100 mg) wasdissolved in chloroform (10 ml) to prepare a solution. Triethylamine(0.3 ml), 4-tert-butylphenylboranic acid (100 mg), and copper(II)acetate (50 mg) were then added to the solution, and the mixture wasstirred at room temperature for 3 days. The insolubles were removed byfiltration, and the solvent was then removed by evaporation under thereduced pressure. The residue was purified by thin-layer chromatographyon silica gel using chloroform/acetone for development to give the titlecompound (21 mg, yield 15%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.49 (m, 1H), 7.59 (s, 1H), 7.44 (s, 1H),7.34 (d, J=8.8 Hz, 2H), 7.07 (d, J=9.0 Hz, 2H), 7.04 (d, J=8.8 Hz, 2H),7.02 (d, J=9.3 Hz, 2H), 6.50 (d, J=4.4 Hz, 1H), 4.05 (s, 3H), 4.05 (s,3H), 3.34 (s, 3H), 1.33 (s, 9H) Mass spectrometric value (m/z): 443[M+H]⁺

Compound 21:4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxy-quinolin-7-ol

[4-(7-Benzyloxy-6-methoxy-4-quinolyloxy)phenyl](4-tert-butylphenyl)amine(starting compound 2) (400 mg) was dissolved in N,N-dimethylformamide(10 ml) to prepare a solution. Triethylamine (2 ml) and 20% palladiumhydroxide (0.58 g) were then added to the solution, and the mixture wasstirred in a hydrogen atmosphere at room temperature overnight. Theinsolubles were removed by filtration, and the solvent was then removedby evaporation under the reduced pressure. Water and ethyl acetate wereadded to the crude, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine and was dried over sodiumsulfate. The solvent was removed by evaporation under the reducedpressure, and the residue was purified by chromatography on silica gelusing chloroform/acetone for development to give the title compound (205mg, yield 62%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.49 (d, J=5.2 Hz, 1H), 7.60 (s, 1H), 7.52(s, 1H), 7.32 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.8 Hz, 2H), 7.07 (d, J=9.3Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.45 (d, J=5.4 Hz, 1H), 5.68 (s, 1H),4.08 (s, 3H), 1.32 (s, 9H) Mass spectrometric value (m/z): 415 [M+H]⁺

Compound 22:(4-Tert-butylphenyl)-{4-[7-(2-chloroethoxy)-6-methoxyquinolin-4-yloxy]phenyl}amine

4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-ol (Compound21) (60 mg) (starting compound A) was dissolved in N,N-dimethylformamide(2 ml) to prepare a solution. Potassium carbonate (200 mg) and1-bromo-2-chloroethylene (0.1 ml) (starting compound B) were then addedto the solution, and the mixture was stirred at room temperature for 8hr. Water and ethyl acetate were added to the reaction solution, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine and was dried over sodium sulfate. The solvent wasremoved by evaporation under the reduced pressure, and the crude waswashed with methanol for purification to give the title compound (22 mg,yield 32%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.49 (d, J=5.1 Hz, 1H), 7.60 (s, 1H), 7.41(s, 1H), 7.33 (d, J=8.6 Hz, 2H), 7.12 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.3Hz, 2H), 7.06 (d, J=8.6 Hz, 2H), 6.49 (d, J=5.4 Hz, 1H), 5.69 (s, 1H),4.45 (t, J=6.1 Hz, 2H), 4.05 (s, 3H), 3.96 (t, J=6.3 Hz, 2H), 1.33 (s,9H) Mass spectrometric value (m/z): 975 [2M+Na]⁺

Compound 24:(4-Tert-butylphenyl)-{4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yloxy]phenyl}amine

(4-Tert-butylphenyl)-{4-[7-(3-chloropropoxy)-6-methoxy-4-quinolyloxy]phenyl}amine(40 mg) (starting compound A) was dissolved in N,N-dimethylformamide (1ml) to prepare a solution. Morpholine (30 μl) (starting compound B) wasthen added to the solution, and the mixture was stirred at 70° C. for 2days. Water and ethyl acetate were added to the reaction solution, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine and was dried over sodium sulfate. The solvent wasremoved by evaporation under the reduced pressure, and the residue waspurified by thin-layer chromatography on silica gel usingchloroform/methanol for development to give the title compound (12 mg,yield 27%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.47 (d, J=5.4 Hz, 1H), 7.57 (s, 1H), 7.43(s, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.11 (d, J=9.0 Hz, 2H), 7.07 (d, J=9.3Hz, 2H), 7.05 (d, J=8.8 Hz, 2H), 6.47 (d, J=5.4 Hz, 1H), 5.71 (s, 1H),4.27 (t, J=6.6 Hz, 2H), 4.03 (s, 3H), 3.72 (m, 4H), 2.58 (t, J=7.1 Hz,2H), 2.49 (m, 4H), 2.13 (tt, J=6.8, 7.1 Hz, 2H), 1.32 (s, 9H) Massspectrometric value (m/z): 542 [M+H]⁺

Compound 30: 4-[4-(4-Tert-butylphenoxy)phenoxy]-6,7-dimethoxyquinoline

4-(6,7-Dimethoxy-4-quinolyloxy)phenol (starting compound 8) (24 mg) wasdissolved in chloroform (2 ml) to prepare a solution. Triethylamine (0.3ml), 4-tert-butylphenylboranic acid (50 mg), and copper(II) acetate (90mg) were added to the solution, and the mixture was stirred at roomtemperature for 4 days. The insolubles were removed by filtration, andthe solvent was then removed by evaporation under the reduced pressure.The residue was purified by thin-layer chromatography on silica gelusing chloroform/acetone for development to give the title compound (20mg, yield 58%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.50 (d, J=5.1 Hz, 1H), 7.57 (s, 1H), 7.44(s, 1H), 7.38 (d, J=8.8 Hz, 2H), 7.15 (d, J=8.8 Hz, 2H), 7.09 (d, J=9.0Hz, 2H), 6.99 (d, J=8.8 Hz, 2H), 6.48 (d, J=5.4 Hz, 1H), 4.05 (s, 3H),4.05 (s, 3H), 1.34 (s, 9H) Mass spectrometric value (m/z): 430 [M+H]⁺

Compound 31:(4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]methylacetate

[4-(Tert-butyl)phenyl]{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-methanone(111 mg) and sodium boron hydride (76 mg) were added to ethanol (15 ml),and the mixture was stirred at room temperature for 3 hr. Water wasadded to the reaction solution, and the mixture was extracted withchloroform. The chloroform layer was dried over anhydrous sodiumsulfate. Chloroform was removed by evaporation under the reducedpressure to give a crude which was then purified by thin-layerchromatography on silica gel using chloroform/ethyl acetate fordevelopment to give(4-tert-butylphenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]methanol(108 mg, yield 97%).

(4-Tert-butylphenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]-methanol(51 mg) was dissolved in N,N-dimethylformamide (10 ml). Triethylamine (1ml) and acetic anhydride (0.5 ml) were then added to the solution, andthe mixture was stirred at room temperature overnight. Water and ethylacetate were added to the reaction solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine and was dried over sodium sulfate. The solvent was removed byevaporation under the reduced pressure, and the residue was purified bythin-layer chromatography on silica gel using chloroform/acetone fordevelopment to give the title compound (35 mg, yield 63%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.50 (m, 1H), 7.54 (s, 1H), 7.52 (s, 1H),7.45 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.3 Hz, 2H), 7.29 (d, J=8.6 Hz, 2H),7.16 (d, J=8.5 Hz, 2H), 6.91 (s, 1H), 6.52 (d, J=5.2 Hz, 1H), 4.06 (s,3H), 4.03 (s, 3H), 2.19 (s, 3H), 1.32 (s, 9H) Mass spectrometric value(m/z): 486 [M+H]⁺

Compound 32: 4-[4-(4-Tert-butylbenzyl)phenoxy]-6,7-dimethoxyquinoline

(4-Tert-butylphenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]-methylacetate (Compound 31) (26 mg) was dissolved in N,N-dimethylformamide (3ml) to prepare a solution. Triethylamine (0.5 ml) and 20% palladiumhydroxide (200 mg) were then added to the solution, and the mixture wasstirred in a hydrogen atmosphere at room temperature for 2 hr. Thereaction solution was filtered, water and ethyl acetate were added tothe filtrate, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine and was dried over sodiumsulfate. The solvent was removed by evaporation under the reducedpressure to give the title compound (18 mg, yield 79%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.48 (d, J=5.1 Hz, 1H), 7.55 (s, 1H), 7.42(s, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 7.15 (d, J=8.0Hz, 2H), 7.10 (d, J=8.3 Hz, 2H), 6.47 (d, J=5.1 Hz, 1H), 4.05 (s, 3H),4.04 (s, 3H), 4.00 (s, 2H), 1.32 (s, 9H) Mass spectrometric value (m/z):428 [M+H]⁺

Compound 37:(4-Tert-butylphenyl)-{4-[6-methoxy-7-(2-morpholin-4-ylethoxy)quinolin-4-yloxy]phenyl}amine

N,N-Dimethylformamide (2 ml) was added to4-{4-[4-(tert-butyl)anilino]phenoxy}-6-methoxy-7-quinolinol (compound21) (100 mg), potassium carbonate (167 mg), and4-(2-chloroethyl)morpholine hydrochloride (70 mg), and the mixture wasstirred at 75 to 80° C. for 6 hr. Water and ethyl acetate were added tothe reaction solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine and was dried over sodiumsulfate, and the solvent was then removed by evaporation under thereduced pressure. The crude thus obtained was purified by thin-layerchromatography on silica gel using chloroform/methanol for developmentto give the title compound (102 mg, yield 81%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.48 (d, J=5.1 Hz, 1H), 7.58 (s, 1H), 7.41(s, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.04-7.13 (m, 6H), 6.48 (d, J=5.1 Hz,1H), 5.69 (br, 1H), 4.34 (t, J=6.0 Hz, 2H), 4.03 (s, 3H), 3.73-3.77 (m,4H), 2.96 (t, J=6.1 Hz, 2H), 2.62-2.66 (m, 4H), 1.33 (s, 9H) Massspectrometric value (m/z): 528 [M+H]⁺

Compound 42:(4-Tert-butylphenyl)-{4-[6-methoxy-7-(1-propylpiperidin-4-ylmethoxy)quinolin-4-yloxy]phenyl}amine

4-Hydroxymethyl piperidine (1.8 g) was dissolved in chloroform (30 ml)to prepare a solution. Triethylamine (4 ml) and di-tert-butyldicarbonate (3.28 g) were then added to the solution, and the mixturewas stirred at room temperature for one hr. The solvent was removed byevaporation under the reduced pressure. The crude thus obtained was thendissolved in ethyl acetate, and the solution was washed with saturatedbrine and was dried over sodium sulfate. The solvent was removed byevaporation under the reduced pressure, and the residue was washed withhexane to give tert-butyl-4-(hydroxymethyl)-1-piperidine carboxylate(2.67 g, yield 83%).

(4-Tert-butylphenyl)-[4-(6-methoxy-7-hydroxy-4-quinolyloxy)-phenyl]amine(compound 21) (0.8 g) (starting compound A),tert-butyl-4-(hydroxymethyl)-1-piperidine carboxylate (0.59 g) (startingcompound B), and triphenylphosphine (0.85 g) were dissolved intetrahydrofuran (25 ml), and the solution was stirred at roomtemperature for 20 min. Under ice cooling, 40% diethyl azodicarboxylate(1.5 ml) was added to the reaction solution, and the mixture was stirredat room temperature overnight. Water and ethyl acetate were added to thereaction solution. The mixture was extracted with ethyl acetate, and theextract was washed with saturated brine and was dried over sodiumsulfate. The solvent was removed by evaporation under the reducedpressure. The crude was dissolved in a 30% trifluoroaceticacid/chloroform solution (15 ml), and the solution was stirred at roomtemperature for 30 min. The solvent was removed by evaporation under thereduced pressure, and the residue was then purified by chromatography onsilica get using chloroform/acetone for development to give(4-tert-butylphenyl)-{4-[6-methoxy-7-(4-piperidinylmethoxy)-4-quinolyloxy]phenyl}amine(0.84 g, yield 86%).

(4-Tert-butylphenyl)-{4-[6-methoxy-7-(4-piperidinylmethoxy)-4-quinolyloxy]phenyl}amine(150 mg) was dissolved in N,N-dimethylformamide (3 ml) to prepare asolution. Potassium carbonate (300 mg) and 1-bromopropane (0.15 ml) werethen added to the solution, and the mixture was stirred at roomtemperature for 4 hr. Water and ethyl acetate were added to the reactionsolution, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine and was dried over sodium sulfate. Thesolvent was removed by evaporation under the reduced pressure, and theresidue was purified by thin-layer chromatography on silica gel usingchloroform/acetone for development to give the title compound (12 mg,yield 7%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.47 (d, J=5.4 Hz, 1H), 7.57 (s, 1H), 7.38(s, 1H), 7.32 (d, J=8.8 Hz, 2H), 7.12 (d, J=9.0 Hz, 2H), 7.07 (d, J=8.8Hz, 2H), 7.05 (d, J=8.5 Hz, 2H), 6.47 (d, J=5.4 Hz, 1H), 4.06 (m, 2H),4.02 (s, 3H), 3.12 (m, 2H), 2.44 (m, 2H), 2.22-1.94 (m, 5H), 1.64 (m,4H), 1.32 (s, 9H), 0.93 (t, J=7.4 Hz, 3H) Mass spectrometric value(m/z): 588 [M+Cl]⁻

Compound 44:[4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl]-(4-morpholin-4-ylphenyl)amine

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (100 mg) and4-bromophenylboronic acid (80 mg) were dissolved in a mixed solutioncomposed of dichloromethane (5 ml) and triethylamine (0.07 ml) toprepare a solution. Copper(II) acetate (50 mg) was added to thesolution, and the mixture was stirred at room temperature for 16 hr. Thestirred mixture was filtered, and the filtrate was then concentrated.The crude thus obtained was purified by chromatography on silica gel togive (4-bromophenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]amine (70mg).

Palladium acetate (18 mg) and (+)-BINAP (70 mg) were dissolved intoluene (1.5 ml), and the solution was stirred at room temperature for 5min. (4-Bromophenyl)-[4-(6,7-dimethoxy-4-quinolyloxy)phenyl]amine (100mg), morpholine (0.15 ml), and cesium carbonate (200 mg) were added inthat order to the reaction solution, and the mixture was stirred at 80°C. overnight. The insolubles were removed by filtration, and the solventwas then removed by evaporation under the reduced pressure. The residuewas purified by thin-layer chromatography on silica gel usingchloroform/acetone to give the title compound (10 mg, yield 9%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.47 (d, J=5.6 Hz, 1H), 7.59 (s, 1H), 7.51(s, 1H), 7.32-6.70 (m, 8H), 6.51 (d, J=5.6 Hz, 1H), 4.06 (s, 3H), 4.06(s, 3H), 3.88 (m, 4H), 3.74-3.38 (m, 4H) Mass spectrometric value (m/z):458 [M+H]⁺

Compound 59:1-{4-[4-(4-Tert-butyl-phenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-morpholin-4-ylpropan-2-ol

N,N-Dimethylformamide (2 ml) was added to4-[4-(4-tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-ol (compound21) (150 mg) (starting compound A) and potassium carbonate (250 mg).Epibromohydrin (46 μl) was added dropwise thereto, and the mixture wasstirred at room temperature for 24 hr. Morpholine (95 μl) (startingcompound B) was added dropwise to the reaction solution, and the mixturewas stirred at 70 to 75° C. for 5 hr. The stirred mixture was extractedwith ethyl acetate, and the extract was washed with saturated brine andwas dried over sodium sulfate. The solvent was then removed byevaporation under the reduced pressure. The crude thus obtained waspurified by thin-layer chromatography on silica gel usingchloroform/methanol for development to give the title compound (179 mg,yield 89%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.48 (d, J=5.4 Hz, 1H), 7.58 (s, 1H), 7.43(s, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.04-7.14 (m, 6H), 6.48 (d, J=5.1 Hz,1H), 5.69 (br, 1H), 4.25-4.32 (m, 1H), 4.15-4.24 (m, 2H), 4.02 (s, 3H),3.69-3.79 (m, 4H), 2.66-2.72 (m, 2H), 2.60-2.64 (m, 2H), 2.48-2.54 (m,2H), 1.32 (s, 9H) Mass spectrometric value (m/z): 558 [M+H]⁺

Compound 70:(R)-1-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-morpholin-4-ylpropan-2-ol

4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-ol (compound21) (230 mg) was dissolved in N,N-dimethylformamide (8 ml) to prepare asolution. Potassium carbonate (300 mg) and p-toluenesulfonic acid(2R)-(−)-glycidyl (0.22 g) were then added to the solution, and themixture was stirred at room temperature overnight. Morpholine (0.5 ml)was added to the reaction solution, and the mixture was further stirredat 70° C. overnight. Water and ethyl acetate were added to the reactionsolution, and the mixture was extracted with ethyl acetate. The extractwas washed with saturated brine and was dried over sodium sulfate. Thesolvent was removed by evaporation under the reduced pressure, and theresidue was purified by thin-layer chromatography on silica gel usingchloroform/acetone for development to give the title compound (200 mg,yield 65%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.48 (d, J=5.4 Hz, 1H), 7.58 (s, 1H), 7.43(s, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.04-7.14 (m, 6H), 6.48 (d, J=5.1 Hz,1H), 5.69 (br, 1H), 4.25-4.32 (m, 1H), 4.15-4.24 (m, 2H), 4.02 (s, 3H),3.69-3.79 (m, 4H), 2.66-2.72 (m, 2H), 2.60-2.64 (m, 2H), 2.48-2.54 (m,2H), 1.32 (s, 9H) Mass spectrometric value (m/z): 558 [M+H]⁺

Compound 71:(s)-1-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-morpholin-4-ylpropan-2-ol

4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-ol (compound21) (210 mg) was dissolved in N,N-dimethylformamide (10 ml) to prepare asolution. Potassium carbonate (500 mg) and p-toluenesulfonic acid(2S)-(+)-glycidyl (0.31 g) were then added to the solution, and themixture was stirred at room temperature overnight. Morpholine (0.5 ml)was added to the reaction solution, and the mixture was stirred at 70°C. for additional 9 hr. Water and ethyl acetate were added to thereaction solution, and the mixture was extracted with ethyl acetate. Theextract was washed with saturated brine and was dried over sodiumsulfate. The solvent was removed by evaporation under the reducedpressure, and the residue was purified by thin-layer chromatography onsilica gel using chloroform/acetone for development to give the titlecompound (180 mg, yield 64%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.48 (d, J=5.4 Hz, 1H), 7.58 (s, 1H), 7.43(s, 1H), 7.33 (d, J=8.8 Hz, 2H), 7.04-7.14 (m, 6H), 6.48 (d, J=5.1 Hz,1H), 5.69 (br, 1H), 4.25-4.32 (m, 1H), 4.15-4.24 (m, 2H), 4.02 (s, 3H),3.69-3.79 (m, 4H), 2.66-2.72 (m, 2H), 2.60-2.64 (m, 2H), 2.48-2.54 (m,2H), 1.32 (s, 9H) Mass spectrometric value (m/z): 558 [M+H]⁺

Compound 75:[4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl]-(4,5-dimethylthiazol-2-yl)amine

4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (200 mg) was dissolved inethanol (30 ml) to prepare a solution. 4-Chlorobenzoyl isothiocyanate(173 mg) was added to the solution, and the mixture was stirred at roomtemperature for 3 hr. After the completion of the reaction, the solventwas removed by evaporation. The crude thus obtained was purified bychromatography on silica gel using chloroform/acetone for development togiveN-(4-chlorobenzoyl)-N′-4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl]thiourea(313 mg, yield 94%).

This compound was added to a 3 N aqueous sodium hydroxide solution (10ml), and the mixture was stirred with heating at 100° C. for 10 min. Theheating was stopped, and the reaction solution was acidified by theaddition of concentrated hydrochloric acid and was then rendered weaklyalkaline by the addition of aqueous ammonia. The precipitate in thesolution was collected by filtration while washing with water to giveN-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}thiourea (200 mg, yield 89%).

N-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}thiourea (50 mg) wasdissolved in dimethylformamide (5 ml) to prepare a solution.Triethylamine (43 mg) and 3-bromo-2-butanone (43 mg) were added to thesolution, and the mixture was stirred at room temperature for 3 hr.Water and ethyl acetate were added to the reaction solution, and themixture was extracted with ethyl acetate. The extract was then washedwith saturated brine and was dried over anhydrous sodium sulfate, andthe solvent was removed by evaporation under the reduced pressure. Thecrude thus obtained was purified by column chromatography on silica gelusing chloroform/methanol for development to give the title compound (42mg, yield 73%).

¹H-NMR (CDCl₃, 400 MHz): 2.14 (s, 2H), 2.18 (s, 4H), 3.97 (s, 3H), 3.98(s, 3H), 6.39 (d, J=5.4 Hz, 1H), 7.07 (d, J=8.8 Hz, 2H), 7.35 (s, 1H),7.35 (d, J=8.8 Hz, 2H), 7.50 (s, 1H), 8.40 (d, J=5.4 Hz, 1H) Massspectrometric value (m/z): 408 [M+1]⁺

Compound 76:5-[4-(6,7-Dimethoxyquinolin-4-yloxy)phenylamino]-3-phenyl-3H-[1,3,4]oxazol-2-one

4-(6,7-Dimethoxy-4-quinolyloxy)aniline (310 mg) was dissolved intriethylamine/chloroform (5 ml/20 ml) to prepare a solution. Triphosgene(350 mg) was then added to the solution, and the mixture was stirred atroom temperature for 30 min. Phenylhydrazine hydrochloride (180 mg) wasadded to the reaction solution, and the mixture was stirred at roomtemperature for additional 30 min. Water and ethyl acetate were added tothe reaction solution, and the mixture was extracted with ethyl acetate.The extract was washed with saturated brine and was dried over sodiumsulfate. The solvent was removed by evaporation under the reducedpressure, and the residue was purified by thin-layer chromatography onsilica gel using chloroform/acetone for development to giveN1-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-2-phenyl-1-hydrazinecarboxamide(270 mg, yield 60%).

N1-{4-[(6,7-Dimethoxy-4-quinolyl)oxy]phenyl}-2-phenyl-1-hydrazinecarboxamide(34 mg) was dissolved in chloroform (5 ml) to prepare a solution.Triethylamine (1 ml) and triphosgene (77 mg) were then added to thesolution, and the mixture was stirred at room temperature for 2 hr.Water and ethyl acetate were added to the reaction solution, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine and was dried over sodium sulfate. The solvent wasremoved by evaporation under the reduced pressure, and the residue waspurified by thin-layer chromatography on silica gel usingchloroform/methanol for development to give the title compound (6 mg,yield 17%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 8.52 (d, J=5.1 Hz, 1H), 7.72-7.66 (m, 4H),7.50 (s, 1H), 7.45 (m, 2H), 7.41 (s, 1H), 7.39 (d, J=9.0 Hz, 2H), 7.20(m, 1H), 6.60 (d, J=5.1 Hz, 1H), 3.96 (s, 3H), 3.94 (s, 3H) Massspectrometric value (m/z): 455 [M−H]⁻

Compound 77:(4-Tert-butylcyclohexyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amine

4-(6,7-Dimethoxy-4-quinolyloxy)aniline (300 mg) was dissolved inN,N-dimethylformamide (10 ml) to prepare a solution.4-Tert-butylcyclohexanone (200 mg) was then added to the solution, andthe mixture was stirred at 60° C. for one hr. The reaction solution wascooled to room temperature before sodium triacetoxy borohydride (400 mg)was added thereto. The mixture was then stirred at room temperature for3 hr. Water and ethyl acetate were added to the reaction solution, andthe mixture was extracted with ethyl acetate. The extract was washedwith saturated brine and was dried over sodium sulfate. The solvent wasremoved by evaporation under the reduced pressure, and the residue waspurified by chromatography on silica gel using chloroform/acetone fordevelopment to give the title compound (50 mg, yield 11%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.45 (m, 1H), 7.59 (s, 1H), 7.48 (s, 1H),7.02-6.96 (m, 2H), 6.70-6.62 (m, 2H), 6.48 (m, 1H), 4.05 (s, 6H), 3.18(m, 1H), 2.25-1.05 (m, 9H), 0.88 (m, 9H) Mass spectrometric value (m/z):435 [M+H]⁺

Compound 78:(4-Tert-butylphenyl)-{4-[6-methoxy-7-(2-morpholin-4-ylethoxy)quinazolin-4-yloxy]phenyl}amine

4-{4-[4-(Tert-butyl)anilino]phenoxy}-6-methoxy-7-quinazolinol (startingcompound 11) (100 mg), potassium carbonate (50 mg), and4-(2-chloroethyl)morpholine hydrochloride (67 mg) were added toN,N-dimethylformamide (2 ml), and the mixture was stirred at 80° C.overnight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine and was dried over sodium sulfate. The solvent was thenremoved by evaporation under the reduced pressure. The crude thusobtained was purified by thin-layer chromatography on silica gel usingchloroform/methanol for development to give the title compound (120 mg,yield 94%).

¹H-NMR (DMSO-d₆, 400 MHz): δ 8.54 (s, 1H), 8.09 (s, 1H), 7.55 (s, 1H),7.41 (s, 1H), 7.28 (d, J=8.5 Hz, 2H), 7.12 (m, 4H), 7.04 (d, J=8.8 Hz,2H), 4.32 (t, J=5.6 Hz, 2H), 3, 97 (s, 3H), 3.60 (m, 4H), 2.80 (t, J=5.9Hz, 2H), 2.53 (m, 4H), 1.27 (s, 9H) Mass spectrometric value (m/z): 527[M−H]⁻

Compound 79:(4-Tert-butylphenyl)-{2-fluoro-4-[6-methoxy-7-(2-morpholin-4-ylethoxy)quinolin-4-yloxy]phenyl}amine

4-{4-[4-(Tert-butyl)anilino]-3-fluorophenoxy}-6-methoxy-7-quinolinol(starting compound 6) (1.75 g), potassium carbonate (2.80 g), and4-(2-chloroethyl)morpholine hydrochloride (1.13 g) were added toN,N-dimethylformamide (20 ml), and the mixture was stirred at 80° C.overnight. Water was added to the reaction solution, and the mixture wasextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine and was dried over sodium sulfate. The solvent was thenremoved by evaporation under the reduced pressure. The crude thusobtained was purified by chromatography on silica gel usingchloroform/methanol for development to give the title compound (1.44 g,yield 64%).

¹H-NMR (CDCl₃, 400 MHz): δ 8.50 (d, J=5.4 Hz, 1H), 7.53 (s, 1H), 7.41(s, 1H), 7.31-7.38 (m, 3H), 7.09 (d, J=8.5 Hz, 2H), 6.97 (m, 1H), 6.88(m, 1H), 6.51 (d, J=5.4 Hz, 1H), 5.74 (br, 1H), 4.34 (t, J=5.9 Hz, 2H),4.03 (s, 3H), 3.76 (m, 4H), 2.96 (t, J=5.9 Hz, 2H), 2.64 (m, 4H), 1.33(s, 9H) Mass spectrometric value (m/z): 546 [M+H]⁺

Compound 87:1-(3,3-Dimethyl-butyl)-3-{2-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea

4-[(7-Benzyloxy-6-methoxy-4-quinolyl)oxy]-2-fluoro-aniline (3.0 g) wasdissolved in anhydrous chloroform (100 ml) to prepare a solution.Triethylamine (3.9 g) was added to the solution, and a solution oftriphosgene (2.3 g) in anhydrous chloroform (5 ml) was then addedthereto. The mixture was stirred at room temperature for 30 min.Subsequently, a solution of 3,3-dimethylbutylamine (1.6 g) in anhydrouschloroform (5 ml) was added thereto, and the mixture was stirred at roomtemperature for additional 1 hr. A saturated sodium hydrogencarbonatesolution was added thereto, and the mixture was stirred. The organiclayer was then separated, was washed with saturated brine, and was driedover anhydrous sodium sulfate. The solvent was removed by evaporationunder the reduced pressure. The residue was purified by columnchromatography on silica gel, and1-[4-([7-benzyloxy-6-methoxy-quinolin-4-yloxy]-2-fluorophenyl)-3-(3,3-dimethyl-butyl)urea(3.9 g, yield 97%) was obtained from the fraction of chloroform:methanol (98:2).

¹H-NMR (CDCl₃, 400 MHz): 0.93 (s, 9H), 1.43-1.47 (m, 2H), 3.26-3.31 (m,2H), 4.01 (s, 3H), 4.78 (brs, 1H), 5.30 (s, 2H), 6.45 (d, J=5.4 Hz, 1H),6.57 (brs, 1H), 6.88-6.95 (m, 2H), 7.28-7.49 (m, 5H), 7.44 (s, 1H), 7.50(s, 1H), 8.14 (t, J=8.8 Hz, 1H), 8.45 (d, J=5.4 Hz, 1H)

1-[4-([7-Benzyloxy-6-methoxy-quinolin-4-yloxy]-2-fluorophenyl)-3-(3,3-dimethyl-butyl)urea(11 g) prepared above was suspended in trifluoroacetic acid (20 ml) andmethanesulfonic acid (1 ml), and the suspension was heated under refluxfor 1 hr. The solvent was removed by evaporation under the reducedpressure. Water was added to the residue, and the solution was adjustedto a pH value of substantially 7 by the addition of a 10% sodiumhydroxide solution. The resultant precipitate was collected byfiltration to give1-(3,3-dimethyl-butyl)-3-[2-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-urea.Next, N,N-dimethylformamide (2 ml) was added to the urea (103 mg)(starting compound A), potassium carbonate (166 mg), and4-(2-chloroethyl)morpholine hydrochloride (69 mg) (starting compound B),and the mixture was stirred at 75 to 80° C. for 16 hr. Water and ethylacetate were added to the reaction solution, and the mixture wasextracted with ethyl acetate. The extract was washed with saturatedbrine and was dried over sodium sulfate, and the solvent was thenremoved by evaporation under the reduced pressure. The crude thusobtained was purified by thin-layer chromatography on silica gel usingchloroform/methanol for development to give the title compound (47.7 mg,yield 37%).

¹H-NMR (CDCl₃+CD₃OD, 400 MHz): 0.96 (s, 9H), 1.45-1.51 (m, 2H), 2.72(br, 4H), 3.02 (t, J=5.6 Hz, 2H), 3.28-3.34 (m, 2H), 3.78-3.81 (m, 4H),4.02 (s, 3H), 4.40 (t, J=5.6 Hz, 2H), 5.16 (br, 1H), 6.51 (d, J=5.6 Hz,1H), 6.89 (dd, J=2.7, 11.2 Hz, 1H), 6.91 (br, 1H), 6.95-6.97 (m, 1H),7.52 (s, 1H), 7.55 (s, 1H), 8.24 (dd, J=9.0, 9.0 Hz, 1H), 8.46 (d, J=5.6Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 541 (M⁺+1)

1-(3,3-Dimethyl-butyl)-3-{2-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-ureahydrochloride

1-(3,3-Dimethyl-butyl)-3-{2-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea(42.7 mg) was dissolved in chloroform (1 ml) and methanol (1 ml) toprepare a solution. To the solution was added 10 drops of 10% hydrogenchloride-methanol with a Pasteur pipette. The mixture was concentratedby an evaporator, and the concentrate was dried by means of a vacuumpump to give a hydride compound (48.9 mg).

¹H-NMR (CDCl₃+CD₃OD, 400 MHz): 0.96 (s, 9H), 1.45-1.51 (m, 2H),3.22-3.32 (m, 4H), 3.71-3.80 (m, 4H), 4.00-4.10 (m, 5H), 4.18-4.28 (m,2H), 4.94 (br, 2H), 6.84 (d, J=5.1 Hz, 1H), 6.97 (d, J=9.0 Hz, 2H), 7.64(s, 1H), 8.01 (s, 1H), 8.38 (t, J=9.0 Hz, 1H), 8.57 (d, J=4.6 Hz, 1H)Mass spectrometric value (ESI-MS, m/z): 563 (M+Na)⁺

Compound 99:1-(3,3-Dimethyl-butyl)-3-{2-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl{-urea

A crude product of1-(3,3-dimethyl-butyl)-3-[2-fluoro-4-(7-hydroxy-6-methoxy-quinolin-4-yloxy)-phenyl]-ureawas dissolved in dimethylformamide (100 ml) to prepare a solution.Potassium carbonate (18 g) and 1-bromo-2-chloroethane (11 g) were addedto the solution, and the mixture was stirred at room temperature for 20hr. The mixture was extracted with ethyl acetate, was then washed withsaturated brine, and was dried over anhydrous sodium sulfate. Thesolvent was removed by evaporation under the reduced pressure. Theresidue was washed with a mixed solvent of n-hexane: ethyl acetate(2: 1) and was then collected by filtration to give1-{4-[7-(2-chloroethoxy)-6-methoxy-quinolin-4-yloxy]-2-fluorophenyl}-3-(3,3-dimethyl-butyl)urea(7.7 g, yield 74%).

¹H-NMR (CDCl₃, 400 MHz): 0.94 (s, 3H), 1.44-1.48 (m, 2H), 3.26-3.32 (m,2H), 3.91-3.95 (m, 2H), 4.01 (s, 3H), 4.41-4.45 (m, 2H), 4.79-4.81 (m,1H), 6.47 (d, J=5.4 Hz, 1H), 6.55-6.57 (m, 1H), 6.89-6.96 (m, 2H), 7.40(s, 1H), 7.51 (s, 1H), 8.10 (t, J=8.8 Hz, 1H), 8.47 (d, J=5.4 Hz, 1H)

N,N-Dimethylformamide (80 ml) was added to the urea (1.98 g) (startingcompound A), potassium carbonate (5 eq, 2.82 g), and piperidine (5 eq,2.02 ml) (starting compound B), and the mixture was stirred at 70 to 75°C. for 17 hr. Piperidine (2 eq, 0.8 ml) (starting compound B) was addedthereto. The mixture was further stirred at 70 to 75° C. for 23 hr.Water and ethyl acetate were added to the reaction solution, and themixture was extracted with ethyl acetate. The extract was washed withsaturated brine and was dried over sodium sulfate, and the solvent wasthen removed by evaporation under the reduced pressure. The crude thusobtained was purified by chromatography on alumina (grade III) usingchloroform/methanol for development to give the title compound (1.69 g,yield 78%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.95 (s, 9H), 1.43-1.52 (m, 4H), 1.62-1.70(m, 4H), 2.53-2.62 (m, 4H), 2.92 (t, J=5.9 Hz, 2H), 3.24-3.31 (m, 2H),4.02 (s, 3H), 4.32 (t, J=5.9 Hz, 2H), 6.48 (d, J=5.4 Hz, 1H), 6.87-6.97(m, 2H), 7.38 (s, 1H), 7.52 (s, 1H), 8.19-8.26 (m, 1H), 8.43 (d, J=5.4Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 539 (M+1)

1-(3,3-Dimethyl-butyl)-3-{2-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-ureahydrochloride

Methanol (20 ml) and chloroform (2 ml) were added to1-(3,3-dimethyl-butyl)-3-{2-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-ureato prepare a solution. Hydrogen chloride-methanol was added to thesolution, and the mixture was acidified and was concentrated. Diethylether was added to the residue, and mixture was filtrated to give thetitle compound (1.75 g, yield 91%).

¹H-NMR (CDCl₃, 400 MHz): δ 0.93 (s, 9H), 1.46-1.52 (m, 2H), 1.78-1.96(m, 4H), 2.13-2.27 (m, 2H), 3.03-3.12 (m, 2H), 3.21-3.27 (m, 2H),3.68-3.83 (m, 4H), 4.05 (s, 3H), 4.87-4.94 (m, 2H), 6.82 (d, J=6.6 Hz,1H), 6.87-6.96 (m, 2H), 7.58 (s, 1H), 7.97 (s, 1H), 8.30-8.33 (m, 1H),8.56 (d, J=6.8 Hz, 1H)

Mass spectrometric value (ESI-MS, m/z): 539 (M+1)

Compound 101:1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea

4-[(6,7-Dimethoxy-quinolyl)oxy]aniline (2 g) was dissolved in chloroform(100 ml) (starting compound A) to prepare a solution. Triethylamine (2ml) was added to the solution. A solution of triphosgene (1 g) inchloroform (4 ml) was added dropwise thereto, and the mixture wasstirred at room temperature for 30 min. 3,3-Dimethylbutylamine (750 mg)(starting compound B) was added thereto, and the mixture was stirred atroom temperature for 5 hr. Water and chloroform were added to thereaction solution, and the mixture was extracted with chloroform. Theextract was washed with saturated brine and was dried over sodiumsulfate. The solvent was then removed by evaporation under the reducedpressure. The crude thus obtained was purified by chromatography onsilica gel using chloroform/acetone for development to give the titlecompound (1.70 g, yield 59%).

¹H-NMR (CDCl₃, 400 MHz): 0.93 (s, 9H), 1.42-1.46 (m, 2H), 3.27-3.32 (m,2H), 4.03 (s, 3H), 4.03 (s, 3H), 5.03 (br, 1H), 6.44 (d, J=5.3 Hz, 1H),7.11 (d, J=9.0 Hz, 2H), 7.41 (s, 1H), 7.43 (d, J=8.8 Hz, 2H), 7.55 (s,1H), 8.46 (d, J=5.1 Hz, 1H), 8.84 (br, 1H) Mass spectrometric value(ESI-MS, m/z): 424 (M⁺+1)

1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-ureahydrochloride

Methanol (20 ml) and chloroform (2 ml) were added to1-[4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-ureato prepare a solution. The solution was acidified by the addition ofhydrogen chloride-methanol, and the acidified solution was concentrated.Diethyl ether was added to the residue, and the mixture was filtrated togive the title compound (1.75 g, yield 91%).

¹H-NMR (CDCl₃, 400 MHz): 0.92 (s, 9H), 1.45-1.49 (m, 2H), 3.24-3.30 (m,2H), 4.10 (s, 3H), 4.14 (s, 3H), 5.98 (br, 1H), 6.48 (d, J=6.6 Hz, 1H),7.02 (d, J=9.0 Hz, 2H), 7.65 (s, 1H), 7.72 (d, J=9.0 Hz, 2H), 7.88 (s,1H), 8.18 (d, J=6.6 Hz, 1H), 8.84 (br, 1H) Mass spectrometric value(ESI-MS, m/z): 424 (M⁺+1)

Compounds 5, 20, 21, 22, 24, 30, 31, 32, 37, 42, 44, 59, 70, 71, 75, 76,77, 78, 79, 87, 99 and 101 had the following respective chemicalstructures. Compound No. Structure of compound 5

20

21

22

24

30

31

32

37

42

44

59

70

71

75

76

77

78

79

87

99

101

The following compounds were synthesized in the same manner as in theSynthesis Examples of the above compounds.

Compound No. Name of Compound

-   1: [4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl]-(4-methoxyphenyl)-amine-   2: [4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl]-(4-vinylphenyl)amine-   3: Biphenyl-4-yl-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amine-   4: [4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl]-(4-fluorophenyl)amine-   6:    [4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl]-(4-trifluoromethoxy-phenyl)amine-   7:    (4-Benzyloxyphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amine-   8: (4-Butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amine-   9:    [4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl]-(4-isopropylphenyl)-amine-   10:    (4-Cyclohexylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]-amine-   11:    (4-Tert-butylphenyl)-[2-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amine-   12:    (4-Tert-butylphenyl)-[3-chloro-4-(6,7-dimethoxyquinolin-4-yloxy)phenyl]amine-   13:    (4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methylphenyl]amine-   14:    (4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-methoxyphenyl]amine-   15:    (4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-methoxyphenyl]amine-   16:    (4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)-2,3-dimethylphenyl]amine-   17:    (4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)-2,5-dimethylphenyl]amine-   18:    (4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenyl]amine-   19:    (4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)-2-fluorophenyl]amine-   23:    (4-Tert-butylphenyl)-{4-[7-(3-chloropropoxy)-6-methoxyquinolin-4-yloxy]phenyl}amine-   25:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(4-morpholin-4-ylbutoxy)-quinolin-4-yloxy]phenyl}amine-   26:    3-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}propionamide-   27:    (4-Tert-butylphenyl)-(4-{6-methoxy-7-[2-(1-methylpyrrolidin-2-yl)ethoxy]quinolin-4-yloxy}phenyl)amine-   28:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(2-methylthiazol-4-ylmethoxy)quinolin-4-yloxy]phenyl}amine-   29:    (4-Tert-butylphenyl)-(4-{6-methoxy-7-[4-(4-methylpiperazin-1-yl)butoxy]quinolin-4-yloxy}phenyl)amine-   33:    (4-Tert-butylphenyl)-(4-{6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinolin-4-yloxy}phenyl)amine-   34:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)-quinolin-4-yloxy]phenyl}amine-   35:    (4-Tert-butylphenyl)-(4-{6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yloxy}phenyl)amine-   36:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(4-piperidin-1-ylbutoxy)-quinolin-4-yloxy]phenyl}amine-   38:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(2-piperidin-1-ylethoxy)-quinolin-4-yloxy]phenyl}amine-   39:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(2-pyrrolidin-1-ylethoxy)-quinolin-4-yloxy]phenyl}amine-   40:    N1-[4-(Tert-butyl)phenyl]-4-({7-[2-(dimethylamino)ethoxy]-6-methoxy-4-quinolyl}oxy)aniline-   41:    N1-[4-(Tert-butyl)phenyl]-4-({7-[2-(diethylamino)ethoxy]-6-methoxy-4-quinolyl}oxy)aniline-   43:    (3,4-Dimethoxyphenyl)-[4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]amine-   45:    (4-Tert-butylphenyl)-(4-{6-methoxy-7-[2-(4-methyl-[1,4]diazepin-1-yl)ethoxy]quinolin-4-yloxy}phenyl)amine-   46:    N1-[4-(Tert-butyl)phenyl]-4-({7-[3-(dimethylamino)propoxy]-6-methoxy-4-quinolyl}oxy)aniline-   47:    N1-[4-(Tert-butyl)phenyl]-4-({7-[3-(diethylamino)propoxy]-6-methoxy-4-quinolyl}oxy)aniline-   48:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)phenoxy]-6-methoxy-quinolin-7-yloxy}ethyl)-(2-hydroxyethyl)amino]ethanol-   49:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)phenoxy]-6-methoxy-quinolin-7-yloxy}ethyl)methylamino]ethanol-   50:    {4-[7-(2-Azepan-1-ylethoxy)-6-methoxyquinolin-4-yloxy]phenyl}-(4-tert-butylphenyl)amine-   51:    2-[(3-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxy-quinolin-7-yloxy}propyl)-(2-hydroxyethyl)amino]ethanol-   52:    2-[(3-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxy-quinolin-7-yloxy}propyl)methylamino]ethanol-   53:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)-quinolin-4-yloxy]phenyl}amine-   54:    {4-[7-(3-Azepan-1-ylpropoxy)-6-methoxyquinolin-4-yloxyl]-phenyl}-(4-tert-butylphenyl)amine-   55:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(1-methylpiperidin-2-ylmethoxy)quinolin-4-yloxy]phenyl}amine-   56:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(1-methylpiperidin-3-ylmethoxy)quinolin-4-yloxy]phenyl}amine-   57:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(5-vinyl-1-azabicyclo-[2.2.2]oct-2-ylmethoxy)quinolin-4-yloxy]phenyl}amine-   58:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(1-methylpyrrolidin-2-ylmethoxy)quinolin-4-yloxy]phenyl}amine-   60:    1-{4-[4-(4-Tert-butyl-phenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-diethylaminopropan-2-ol-   61:    1-{4-[4-(4-Tert-butyl-phenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-pyrrolidin-1-ylpropan-2-ol-   62:    1-{4-[4-(4-Tert-butyl-phenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-piperidin-1-ylpropan-2-ol-   63:    1-Azepan-1-yl-3-{4-[4-(4-tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}propan-2-ol-   64:    1-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-(4-methylpiperazin-1-yl)propan-2-ol-   65:    1-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-(4-methyl-[1,4]diazepin-1-yl)propan-2-ol-   66:    1-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-ethylaminopropan-2-ol-   67:    1-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxyquinolin-7-yloxy}-3-dimethylaminopropan-2-ol-   68:    (4-Tert-butylphenyl)-(4-{7-[2-(2,6-dimethylmorpholin-4-yl)ethoxy]-6-methoxyquinolin-4-yloxy}phenyl)amine-   69:    (4-Tert-butylphenyl)-(4-{7-[3-(2,6-dimethylmorpholin-4-yl)propoxy]-6-methoxyquinolin-4-yloxy}phenyl)amine-   72:    [4-(6,7-Dimethoxyquinazolin-4-yloxy)phenyl]-(4-isopropyl-phenyl)amine-   73: [4-(6,7-Dimethoxyquinolin-4-yloxy)phenyl]thiophen-3-ylamine-   74:    (4-Tert-butylphenyl)-[4-(6,7-dimethoxyquinazolin-4-yloxy)-phenyl]amine-   80:    (4-Tert-butylphenyl)-{4-[6-methoxy-7-(3-morpholin-4-ylbutoxy)-quinolin-4-yloxy]phenyl}amine-   81:    [1-(2-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxy-quinolin-7-yloxy}ethyl)piperidin-4-yl]methanol-   82:    1-(2-{4-[4-(4-Tert-butylphenylamino)phenoxy]-6-methoxy-quinolin-7-yloxy}ethyl)piperidin-4-ol-   83:    4-{2-[(4-{4-[4-(Tert-butyl)anilino]phenoxy}-6-methoxy-7-quinolyl)-oxy]ethyl}-1,4-oxazinan-4-ium-4-oleate-   84:    N-[4-(Tert-butyl)phenyl]-N-(3-chloro-4-{[6-methoxy-7-(2-morpholinoethoxy)-4-quinolyl]oxy}phenyl)amine-   85:    2-({2-[(4-{4-[4-(Tert-butyl)anilino]phenoxy}-6-methoxy-7-quinolyl)oxy]ethyl}amino)-1-ethanol-   86:    1-[(4-{4-[4-(Tert-butyl)anilino]phenoxy}-7-methoxy-6-quinolyl)-oxy]-3-morpholino-2-propanol-   88:    1-(3,3-Dimethyl-butyl)-3-{2-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-urea    hydrochloride-   89:    1-(3,3-Dimethyl-butyl)-3-{2-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-urea    hydrochloride-   90:    1-(3,3-Dimethyl-butyl)-3-{4-[7-methoxy-6-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea-   91:    1-(3,3-Dimethyl-butyl)-3-{4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea    hydrochloride-   94:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   96:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(4-hydroxy-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   97:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-2-fluoro-phenyl)-urea-   98:    1-(3,3-Dimethyl-butyl)-3-{3-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea-   100:    1-{2-Chloro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   102:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluorophenyl]-3-(3,3-dimethyl-butyl)-urea-   103:    1-[2-Chloro-4-(6,7-dimethoxyquinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   105:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3,5-trimethyl-cyclohexyl)-urea-   106:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-3-(3,3,5-trimethyl-cyclohexyl)-urea-   107:    1-[2-Chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3,5-tri    methyl-cyclohexyl)-urea-   108:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-cyclohexyl)-urea-   109:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-3-(3,3-dimethyl-cyclohexyl)-urea-   110:    1-[2-Chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-cyclohexyl)-urea-   111:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-3-(3,3-dimethyl-butyl)-urea-   112:    1-(3,3-Dimethyl-butyl)-3-{4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea    hydrochloride-   113:    1-(3,3-Dimethyl-butyl)-3-(4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-urea    hydrochloride-   114:    1-{2-Chloro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   115:    1-(2-Chloro-4-{6-methoxy-7-[2-(4-methyl-piperazin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   116:    1-(2-Chloro-4-{7-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   117:    1-(2-Chloro-4-{6-methoxy-7-[2-(4-methyl-piperidin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   119:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   120:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(3,5-dimethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   121:    1-(3,3-Dimethyl-butyl)-3-(4-{6-methoxy-7-[2-(4-phenyl-piperidin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-urea-   122:    1-(4-{7-[2-(4-Benzyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   123:    1-{4-[7-(2-[1,4′]bipiperidineyl-1′-yl-ethoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   124:    1-(3,3-Dimethyl-butyl)-3-(4-{6-methoxy-7-[2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-urea-   125:    1-(2-Chloro-4-{7-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,    3-dimethyl-butyl)-urea-   126:    1-{3-Chloro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   127:    1-(3-Chloro-4-{7-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   128:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-3-fluoro-phenyl)-urea-   129:    1-(3,3-Dimethyl-butyl)-3-{3-fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea-   130:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(2,6-dimethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-2-fluoro-phenyl)-urea-   131:    1-(3,3-Dimethyl-butyl)-3-(2-fluoro-4-{6-methoxy-7-[2-(2,2,6,6-tetramethyl-piperidin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-urea-   132:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(2,6-dimethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-3-fluoro-phenyl)-urea-   133:    1-(3,3-Dimethyl-cyclohexyl)-3-{2-fluoro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-urea-   134:    1-(3,3-Dimethyl-cyclohexyl)-3-(4-{7-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-2-fluoro-phenyl)-urea

For these compounds, chemical structures, starting compounds, synthesismethods, and data for identifying the compounds are as follows. Thenumeral described in the column of the synthesis method indicates thatthe indicated compound has been synthesized according to the SynthesisExample of the indicated compound number. Compound No. Structure ofcompound Starting compound A 1

2

3

4

6

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 1

403 [M + H]⁺ 5 2

399 [M + H]⁺ 5 3

449 [M + H]⁺ 5 4

391 [M + H]⁺ 5 6

457 [M + H]⁺ 5 Compound No. Structure of compound Starting compound A 7

8

9

10

11

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 7

479 [M + H]⁺ 5 8

429 [M + H]⁺ 5 9

415 [M + H]⁺ 5 10

455 [M + H]⁺ 5 11

497 [M + Cl]⁻ 5 Compound No. Structure of compound Starting compound A12

13

14

15

16

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 12

497 [M + Cl]⁻ 5 13

478 [M + Cl]⁻ 5 14

493 [M + Cl]⁻ 5 15

493 [M + Cl]⁻ 5 16

491 [M + Cl]⁻ 5 Com- pound No. Structure of compound Starting compound A17

18

19

23

25

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 17

491 [M + Cl]⁻ 5 18

455 [M − H]⁻ 5 19

445 [M − H]⁻ 5 23

491 [M + H]⁺ 22 25

556 [M + H]⁺ 24 Com- pound No. Structure of compound Starting compound A26

27

28

29

33

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 26

508 [M + Na]⁺ 42 27

526 [M + H]⁺ 42 28

526 [M + H]⁺ 42 29

569 [M + H]⁺ 24 33

563 [M + Na]⁺ 24 Com- pound No. Structure of compound Starting compoundA 34

35

36

38

39

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 34

540 [M + H]⁺ 24 35

555 [M + H]⁺ 24 36

554 [M + H]⁺ 24 38

526 [M + H]⁺ 24 39

512 [M + H]⁺ 24 Com- pound No. Structure of compound Starting compound A40

41

43

45

46

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 40

486 [M + H]⁺ 24 41

514 [M + H]⁺ 24 43

467 [M + Cl]⁻ 5 45

555 [M + H]⁺ 24 46

500 [M + H]⁺ 24 Com- pound No. Structure of compound Starting compound A47

48

49

50

51

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 47

528 [M + H]⁺ 24 48

546 [M + H]⁺ 24 49

516 [M + H]⁺ 24 50

540 [M + H]⁺ 24 51

560 [M + H]⁺ 24 Com- pound No. Structure of compound Starting compound A52

53

54

55

56

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 52

530 [M + H]⁺ 24 53

526 [M + H]⁺ 24 54

554 [M + H]⁺ 24 55

526 [M + H]⁺ 42 56

526 [M + H]⁺ 42 Com- pound No. Structure of compound Starting compound A57

58

60

61

62

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 57

564 [M + H]⁺ 42 58

512 [M + H]⁺ 42 60

544 [M + H]⁺ 59 61

542 [M + H]⁺ 59 62

556 [M + H]⁺ 59

Com- pound No. Structure of Compound Starting compound A 63

64

65

66

67

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 63

570 [M + H]⁺ 59 64

571 [M + H]⁺ 59 65

585 [M + H]⁺ 59 66

516 [M + H]⁺ 59 67

516 [M + H]⁺ 59 Com- pound No. Structure of compound Starting compound A68

69

72

73

74

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 68

556 [M + H]⁺ 24 69

570 [M + H]⁺ 24 72

416 (M + H)+ 5 73

379 (M + H)+ 5 74

430 (M + H)+ 5 Com- pound No. Structure of compound Starting compound A80

81

82

Compound Mass spectrometric Synthesis No. Starting compound B value(m/z) method 80

556 (M + H)+ 24 81

556 (M + H)+ 24 82

542 (M + H)+ 24 Com- pound No. Structure of compound Starting compound A83

84

85

86

88

Compound No. Starting compound B Synthesis method 83

24 84

24 85

24 86

59 88

99 Compound No. Structure of compound 89

90

91

94

96

Compound No. Starting compound A 89

90

91

94

96

Compound No. Starting compound B Synthesis method 89

59 90

87 91

99 94

99 96

99 Compound No. Structure of compound 97

98

100

102

103

Compound No. Starting compound A 97

98

100

102

103

Compound No. Starting compound B Synthesis method 97

99 98

99 100

99 102

101 103

101 Compound No. Structure of compound Starting compound A 105

106

107

108

109

Compound No. Starting compound B Synthesis method 105

101 106

101 107

101 108

101 109

101 Com- pound No. Structure of compound Starting compound A 110

111

112

113

114

Compound No. Starting compound B Synthesis method 110

101 111

101 112

99 113

99 114

99 Compound No. Structure of compound 115

116

117

119

120

Compound No. Starting compound A 115

116

117

119

120

Compound No. Starting compound B Synthesis method 115

99 116

99 117

99 119

99 120

99 Compound No. Structure of compound 121

122

123

124

125

Compound No. Starting compound A 121

122

123

124

125

Compound No. Starting compound B Synthesis method 121

99 122

99 123

99 124

99 125

99

Compound No. Structure of compound 126

127

128

129

130

Compound No. Starting compound A 126

127

128

129

130

Compound No. Starting compound B Synthesis method 126

99 127

99 128

99 129

99 130

101 Compound No. Structure of compound 131

132

133

134

Compound No. Starting compound A 131

132

133

134

Compound No. Starting compound B Synthesis method 131

101 132

101 133

99 134

99Compound 83

¹H-NMR (CDCl₃, 400 MHz): 1.32 (s, 9H), 3.47-3.54 (m, 4H), 3.83-3.89 (m,4H), 3.99 (s, 3H), 4.45-4.50 (m, 2H), 4.83-4.87 (m, 2H), 5.76 (br, 1H),6.49 (d, J=5.1 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 7.06 (d, J=9.0 Hz, 2H),7.12 (d, J=9.0 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H), 7.49 (s, 1H), 7.58 (s,1H), 8.49 (d, J=5.4 Hz, 1H)

Compound 84

¹H-NMR (CDCl₃, 400 MHz): 1.33 (s, 9H), 2.62-2.64 (m, 4H), 2.94 (t, J=5.9Hz, 2H), 3.74-3.77 (m, 4H), 4.004 (s, 3H), 4.33 (t, J=5.9 Hz, 2H), 5.79(s, 1H), 6.37 (d, J=5.1 Hz, 1H), 6.79 (d, J=6.6 Hz, 2H), 6.96 (dd,J=2.7, 8.8 Hz, 1H), 7.07-7.12 (m, 1H), 7.17 (d, J=2.7 Hz, 1H), 7.35 (d,J=8.5 Hz, 2H), 7.42 (s, 1H), 7.61 (s, 1H), 8.48 (d, J=5.4 Hz, 1H)

Compound 85

¹H-NMR (CDCl₃, 400 MHz): 1.32 (s, 9H), 2.89-2.92 (m, 2H), 3.18 (t, J=5.1Hz, 2H), 3.68-3.71 (m, 2H), 4.03 (s, 3H), 4.23 (t, J=5.1 Hz, 2H), 5.72(br, 1H), 6.48 (d, J=5.4 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 7.07 (d, J=8.5Hz, 2H), 7.12 (d, J=9.0 Hz, 2H), 7.33 (d, J=8.5 Hz, 2H), 7.42 (s, 1H),7.58 (s, 1H), 8.48 (d, J=5.4 Hz, 1H)

Compound 86

¹H-NMR (CDCl₃, 400 MHz): 1.33 (s, 9H), 2.52-2.57 (m, 2H), 2.65-2.74 (m,4H), 3.73-3.78 (m, 4H), 4.03 (s, 3H), 4.21 (t, J=5.1 Hz, 2H), 4.27-4.32(m, 1H), 5.71 (s, 1H), 6.51 (d, J=5.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 2H),7.06 (d, J=8.8 Hz, 2H), 7.12 (d, J=9.0 Hz, 2H), 7.33 (d, J=8.8 Hz, 2H),7.49 (s, 1H), 7.63 (s, 1H), 8.49 (d, J=5.6 Hz, 1H) Mass spectrometricvalue (ESI-MS, m/z): 558 (M⁺+1)

Compound 88

¹H-NMR (CDCl₃+CD₃OD, 400 MHz): 0.96 (s, 9H), 1.44-1.50 (m, 2H),2.54-2.61 (m, 2H), 3.04-3.14 (m, 2H), 3.24-3.30 (m, 2H), 3.35-3.42 (m,2H), 3.56-3.64 (m, 2H), 4.00-4.09 (m, 5H), 4.16-4.25 (m, 2H), 4.47 (t,J=6.1 Hz, 2H), 6.81 (d, J=6.6 Hz, 1H), 6.95-7.12 (m, 2H), 7.32 (s, 1H),7.63 (s, 1H), 8.40 (t, J=8.8 Hz, 1H), 8.54 (d, J=6.8 Hz, 1H) Massspectrometric value (ESI-MS, m/z): 555 (M+1)⁺

Compound 89

¹H-NMR (CDCl₃+CD₃OD, 400 MHz): 0.97 (s, 9H), 1.44-1.50 (m, 2H),3.18-3.44 (m, 5H), 3.48-3.68 (m, 2H), 3.80-3.89 (m, 1H), 3.97-4.25 (m,7H), 4.35-4.46 (m, 2H), 4.85 (br, 1H), 6.82 (d, J=6.6 Hz, 1H), 6.99 (d,J=8.8 Hz, 2H), 7.64 (s, 1H), 7.96 (s, 1H), 8.39 (t, J=8.8 Hz, 1H), 8.53(d, J=6.6 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 571 (M+1)⁺

Compound 90

¹H-NMR (CDCl₃, 400 MHz): δ 0.94 (s, 9H), 1.43-1.48 (m, 2H), 2.63-2.68(m, 4H), 2.96 (t, J=5.8 Hz, 2H), 3.26-3.33 (m, 2H), 3.73-3.77 (m, 4H),4.02 (s, 3H), 4.33 (t, J=6.0 Hz, 2H), 4.91-4.96 (m, 1H), 6.44 (d, J=5.4Hz, 1H), 6.96 (br, 1H), 7.08 (d, J=9.0 Hz, 2H), 7.42-7.47 (m, 3H), 7.59(s, 1H), 8.42 (d, J=5.6 Hz, 1H) Mass spectrometric value (ESI-MS, m/z):523 (M+1)

Compound 91

¹H-NMR (CD₃OD, 400 MHz): 0.97 (s, 9H), 1.48-2.02 (m, 8H), 3.19 (m, 2H),3.25 (m, 2H), 3.72-3.80 (m, 4H), 4.12 (s, 3H), 4.76 (m, 2H), 6.94 (d,J=6.8 Hz, 1H), 7.24 (d, J=9.0 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.64 (s,1H), 7.88 (s, 1H), 8.70 (d, J=6.6 Hz, 1H) Mass spectrometric value(ESI-MS, m/z): 521 (M⁺−1)

Compound 94

¹H-NMR (CDCl₃+CD₃OD, 400 MHz): 0.95 (s, 9H), 1.32-1.41 (m, 1H),1.44-1.46 (m, 2H), 1.74-1.77 (m, 4H), 2.03-2.08 (m, 2H), 2.13-2.19 (m,2H), 2.61-2.64 (m, 2H), 3.03-3.07 (m, 2H), 3.27-3.32 (m, 2H), 3.51 (t,J=6.1 Hz, 2H), 4.00 (s, 3H), 4.25 (t, J=6.6 Hz, 2H), 4.83 (br, 1H), 6.43(d, J=5.4 Hz, 1H), 6.78 (s, 1H), 7.11 (d, J=9.0 Hz, 2H), 7.42 (s, 1H),7.43 (d, J=9.0 Hz, 2H), 7.53 (s, 1H), 8.44 (d, J=5.4 Hz, 1H) Massspectrometric value (ESI-MS, m/z): 555 (M+1)⁺

Compound 96

¹H-NMR (CDCl₃, 400 MHz): 0.95 (s, 9H), 1.44-1.48 (m, 2H), 1.58-1.67 (m,2H), 1.93-2.30 (m, 6H), 2.61 (t, J=7.6 Hz, 2H), 2.78-2.86 (m, 2H),3.27-3.35 (m, 2H), 3.72-3.83 (m, 1H), 4.01 (s, 3H), 4.25 (t, J=6.6 Hz,3H), 4.93 (t, J=5.4 Hz, 1H), 6.43 (d, J=5.4 Hz, 1H), 6.92 (s, 1H), 7.10(d, J=8.8 Hz, 2H), 7.41 (s, 1H), 7.44 (d, J=9.0 Hz, 2H), 7.57 (s, 1H),8.43 (d, J=5.4 Hz, 1H)

Compound 97

¹H-NMR (CDCl₃, 400 MHz): δ 0.96 (s, 9H), 1.18 (d, J=6.3 Hz, 6H),1.45-1.51 (m, 2H), 1.95-2.05 (m, 2H), 2.90-3.00 (m, 4H), 3.28-3.35 (m,2H), 3.73-3.81 (m, 2H), 4.01 (s, 3H), 4.37 (t, J=5.8 Hz, 2H), 4.79-4.84(m, 1H), 6.49 (d, J=5.4 Hz, 1H), 6.56-6.60 (m, 1H), 6.91 (dd, J=2.4,11.2 Hz, 1H), 6.96 (d, J=9.0 Hz, 1H), 7.44 (s, 1H), 7.50 (s, 1H), 8.18(t, J=9.0 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H) Mass spectrometric value(ESI-MS, m/z): 567 (M−1)

Compound 98

¹H-NMR (CDCl₃, 400 MHz): δ 0.95 (s, 9H), 1.44-1.49 (m, 2H), 2.63-2.68(m, 4H), 2.96 (t, J=5.8 Hz, 2H), 3.26-3.34 (m, 2H), 3.74-3.78 (m, 4H),4.03 (s, 3H), 4.35 (t, J=5.8 Hz, 2H), 4.90-4.95 (m, 1H), 6.40 (d, J=5.4Hz, 1H), 7.04-7.14 (m, 3H), 7.45 (s, 1H), 7.50-7.55 (m, 1H), 7.58 (s,1H), 8.43 (d, J=5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 539(M−1)

Compound 100

1-{2-Chloro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3.3-dimethyl-butyl)-urea

¹H-NMR (CDCl₃, 400 MHz): 0.97 (s, 9H), 1.42-1.54 (m, 4H), 1.58-1.68 (m,4H), 2.57 (br, 4H), 2.93 (t, J=6.3 Hz, 2H), 3.28-3.36 (m, 2H), 4.01 (s,3H), 4.34 (t, J=6.3 Hz, 2H), 4.74 (s, 1H), 6.47 (d, J=5.4 Hz, 1H), 6.70(s, 1H), 7.10 (dd, J=2.7, 9.0 Hz, 1H), 7.21 (d, J=2.7 Hz, 1H), 7.41 (s,1H), 7.49 (s, 1H), 8.25 (d, J=9.0 Hz, 1H), 8.49 (d, J=5.1 Hz, 1H) Massspectrometric value (ESI-MS, m/z): 555 (M)⁺

Compound 102

¹H-NMR (CDCl₃, 400 MHz): 0.92 (s, 9H), 1.41-1.45 (m, 2H), 3.26-3.32 (m,2H), 4.02 (s, 3H), 4.04 (s, 3H), 5.36 (br, 1H), 6.39 (d, J=5.4 Hz, 1H),7.07-7.13 (m, 2H), 7.40 (s, 1H), 7.49-7.52 (m, 1H), 7.58 (s, 1H), 7.86(br, 1H), 8.44 (d, J=5.4 Hz, 1H)

Compound 103

¹H-NMR (CDCl₃, 400 MHz): 0.95 (s, 9H), 1.45-1.50 (m, 2H), 3.27-3.35 (m,2H), 4.04 (s, 3H), 4.04 (s, 3H), 5.61 (br, 1H), 6.48 (d, J=5.4 Hz, 1H),7.10 (dd, J=2.7, 9.0 Hz, 1H), 7.17 (br, 1H), 7.18 (d, J=2.7 Hz, 1H),7.43 (s, 1H), 7.51 (s, 1H), 8.29 (d, J=9.0 Hz, 1H), 8.49 (d, J=5.4 Hz,1H) Mass spectrometric value (ESI-MS, m/z): 458 (M⁺+1)

Compound 105

¹H-NMR (CDCl₃, 400 MHz): 0.53-2.09 (m, 7H), 0.85 (d, J=6.4 Hz, 3H), 0.90(s, 3H), 0.95 (s, 3H), 3.81-3.89 (m, 1H), 4.02 (s, 6H), 4.71 (d, J=7.8Hz), 6.42 (d, J=5.4 Hz, 1H), 6.80 (s, 1H), 7.08 (d, J=8.8 Hz, 2H), 7.38(s, 1H), 7.39 (d, J=8.8 Hz, 2H), 7.53 (s, 1H), 8.44 (d, J=5.4 Hz, 1H)Mass spectrometric value (ESI-MS, m/z): 464 (M⁺+1)

Compound 106

¹H-NMR (CDCl₃, 400 MHz): 0.51-2.05 (m, 7H), 0.82 (d, J=6.6 Hz, 3H), 0.86(s, 3H), 0.90 (s, 3H), 3.76-3.83 (m, 1H), 3.97 (s, 6H), 4.90 (d, J=8.1Hz, 1H), 6.41 (d, J=5.4 Hz, 1H), 6.73-6.74 (m, 1H), 6.83-6.93 (m, 2H),7.35 (s, 1H), 7.44 (s, 1H), 8.13 (t, J=9.1 Hz, 1H), 8.42 (d, J=5.4 Hz,1H) Mass spectrometric value (ESI-MS, m/z): 482 (M⁺+1)

Compound 107

¹H-NMR (CDCl₃, 400 MHz): 0.58-2.05 (m, 7H), 0.87 (d, J=6.6 Hz, 3H), 0.91(s, 3H), 0.95 (s, 3H), 3.78-3.87 (m, 1H), 4.01 (s, 3H), 4.02 (s, 3H),5.12 (d, J=7.4 Hz, 1H), 6.44 (d, J=5.4 Hz, 1H), 6.98 (s, 1H), 7.07 (dd,J=2.7, 9.0 Hz, 1H), 7.16 (d, J=2.7 Hz, 1H), 7.39 (s, 1H), 7.49 (s, 1H),8.27 (d, J=9.0 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H) Mass spectrometric value(ESI-MS, m/z): 498, 500 (M⁺+1)

Compound 108

¹H-NMR (CDCl₃, 400 MHz): 0.84-2.15 (m, 8H), 0.87 (s, 3H), 0.93 (s, 3H),3.77-3.83 (m, 1H), 4.00 (s, 3H), 4.01 (s, 3H), 5.01 (d, J=7.8 Hz, 1H),6.40 (d, J=5.4 Hz, 1H), 7.01 (d, J=9.0 Hz, 2H), 7.22 (s, 1H), 7.33 (s,1H), 7.35 (d, J=9.0 Hz, 2H), 8.38 (d, J=5.4 Hz, 1H) Mass spectrometricvalue (ESI-MS, m/z): 450 (M⁺+1)

Compound 109

¹H-NMR (CDCl₃, 400 MHz): 0.81-2.03 (m, 8H), 0.86 (s, 3H), 0.90 (s, 3H),3.72-3.80 (m, 1H), 3.97 (s, 3H), 3.98 (s, 3H), 5.02 (d, J=7.8 Hz, 1H),6.41 (d, J=5.4 Hz, 1H), 6.82-6.93 (m, 3H), 7.35 (s, 1H), 7.44 (s, 1H),8.13 (t, J=9.0 Hz, 1H), 8.41 (d, J=5.4 Hz, 1H) Mass spectrometric value(ESI-MS, m/z): 468 (M⁺+1)

Compound 110

¹H-NMR (CDCl₃, 400 MHz): 0.85-2.07 (m, 8H), 3.72-3.83 (m, 1H), 4.01 (s,3H), 4.02 (s, 3H), 5.01 (d, J=7.6 Hz, 1H), 6.44 (d, J=5.4 Hz, 1H), 7.07(dd, J=2.7, 9.0 Hz, 1H), 7.16 (d, J=2.7 Hz, 1H), 7.40 (s, 1H), 7.49 (s,1H), 8.27 (d, J=9.0 Hz, 1H), 8.46 (d, J=5.4 Hz, 1H) Mass spectrometricvalue (ESI-MS, m/z): 484, 486 (M⁺+1)

Compound 111

¹H-NMR (CDCl₃, 400 MHz): 0.96 (s, 9H), 1.45-1.51 (m, 2H), 3.28-3.35 (m,2H), 4.04 (s, 3H), 4.05 (s, 3H), 4.74 (t, J=5.4 Hz, 1H), 6.48-6.53 (m,2H), 6.92-7.00 (m, 2H), 7.42 (s, 1H), 7.51 (s, 1H), 8.17 (t, J=9.0 Hz,1H), 8.50 (d, J=5.4 Hz, 1H)

Compound 112

¹H-NMR (CD₃OD, 400 MHz): 0.85 (s, 9H), 1.32-1.38 (m, 2H), 2.54-2.57 (m,4H), 2.85-2.88 (m, 2H), 3.17-3.23 (m, 2H), 3.64-3.69 (m, 4H), 3.93 (s,3H), 4.23-4.26 (m, 2H), 5.36-5.38 (m, 1H), 6.34 (d, J=5.2 Hz, 1H), 6.99(d, J=8.8 Hz, 2H), 7.39 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 7.47 (s, 1H),7.71 (brs, 1H), 8.36 (d, J=5.2 Hz, 1H) Mass spectrometric value (ESI-MS,m/z): 523 (M⁺+1)

Compound 113

¹H-NMR (CD₃OD, 400 MHz): 0.97 (s, 9H), 1.48 (m, 2H), 3.06 (s, 3H), 3.24(m, 2H), 3.80-4.02 (m, 10H), 4.12 (s, 3H), 4.86 (m, 2H), 6.94 (d, J=6.6Hz, 1H), 7.25 (d, J=8.3 Hz, 2H), 7.61 (d, J=8.8 Hz, 2H), 7.62 (s, 1H),7.87 (s, 1H), 8.70 (d, J=6.6 Hz, 1H) Mass spectrometric value (ESI-MS,m/z): 536 (M⁺−1)

Compound 114

1-{2-Chloro-4-[6-methoxy-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea

¹H-NMR (CDCl₃, 400 MHz): 0.97 (s, 9H), 1.46-1.53 (m, 2H), 2.62-2.67 (m,4H), 2.95 (t, J=6.1 Hz, 2H), 3.29-3.36 (m, 2H), 3.73-3.78 (m, 4H), 4.01(s, 3H), 4.34 (t, J=6.1 Hz, 2H), 4.75 (t, J=5.6 Hz, 1H), 6.48 (d, J=5.1Hz, 1H), 6.70 (s, 1H), 7.10 (dd, J=2.7, 9.0 Hz, 1H), 7.21 (d, J=2.9 Hz,1H), 7.42 (s, 1H), 7.50 (s, 1H), 8.26 (d, J=9.0 Hz, 1H), 8.50 (d, J=5.1Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 557 (M)⁺

Compound 115

¹H-NMR (CDCl₃, 400 MHz): 0.97 (s, 9H), 1.48-1.52 (m, 2H), 1.81 (br, 4H),2.31 (s, 3H), 2.51 (br, 2H), 2.68 (br, 2H), 2.97 (t, J=6.1 Hz, 2H),3.29-3.35 (m, 2H), 4.01 (s, 3H), 4.33 (t, J=6.1 Hz, 2H), 4.75 (br, 1H),6.47 (d, J=5.4 Hz, 1H), 6.71 (s, 1H), 7.11 (dd, J=2.7, 9.0 Hz, 1H), 7.21(d, J=2.7 Hz, 1H), 7.41 (s, 1H), 7.49 (s, 1H), 8.26 (d, J=9.0 Hz, 1H),8.49 (d, J=5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 570(M⁺+1)

Compound 116

¹H-NMR (CDCl₃, 400 MHz): 0.96 (s, 9H), 1.18 (d, J=6.3 Hz, 6H), 1.47-1.52(m, 2H), 1.92-1.97 (m, 2H), 2.88-2.96 (m, 4H), 3.29-3.35 (m, 2H),3.70-3.77 (m, 2H), 4.01 (s, 3H), 4.33 (t, J=6.1 Hz, 2H), 4.97 (t, J=5.4Hz, 1H), 6.48 (d, J=5.4 Hz, 1H), 6.82 (s, 1H), 7.10 (dd, J=2.7, 9.0 Hz,1H), 7.42 (s, 1H), 7.50 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.49 (d, J=5.1Hz, 1H)

Compound 117

¹H-NMR (CDCl₃, 400 MHz): 0.94 (d, J=6.1 Hz, 3H), 0.96 (s, 9H), 1.23-1.26(m, 2H), 1.47-1.51 (m, 2H), 1.64-1.67 (m, 2H), 2.12-2.18 (m, 2H), 2.95(t, J=6.1 Hz, 2H), 3.01-3.04 (m, 2H), 3.29-3.33 (m, 2H), 4.01 (s, 3H),4.32 (t, J=6.1 Hz, 2H), 5.09 (t, J=5.4 Hz, 1H), 6.47 (d, J=5.4 Hz, 1H),6.89 (s, 1H), 7.10 (dd, J=2.7, 9.0 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 7.41(s, 1H), 7.50 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.49 (d, J=5.4 Hz, 1H)

Compound 119

¹H-NMR (CDCl₃, 400 MHz): δ 0.95 (s, 9H), 1.19 (d, J=6.3 Hz, 6H),1.43-1.49 (m, 2H), 2.02 (t, J=9.7 Hz, 2H), 2.93-3.01 (m, 4H), 3.26-3.33(m, 2H), 3.74-3.84 (m, 2H), 4.02 (s, 3H), 4.38 (t, J=5.7 Hz, 2H),4.90-4.96 (m, 1H), 6.44 (d, J=5.6 Hz, 1H), 6.97 (br, 1H), 7.08 (d, J=8.8Hz, 2H), 7.47 (d, J=8.8 Hz, 2H), 7.51 (s, 1H), 7.56 (s, 1H), 8.40 (d,J=5.6 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 551 (M+1), 549(M−1)

Compound 120

¹H-NMR (CDCl₃, 400 MHz): δ 0.90 (d, J=6.1 Hz, 6H), 0.95 (s, 9H),0.94-1.10 (m, 2H), 1.42-1.48 (m, 2H), 1.74-1.95 (m, 3H), 3.04-3.16 (m,3H), 3.26-3.33 (m, 2H), 4.00 (s, 3H), 4.39-4.45 (m, 2H), 4.93 (br, 1H),6.39 (d, J=5.1 Hz, 1H), 6.91 (br, 1H), 7.05 (d, J=9.0 Hz, 2H), 7.39-7.44(m, 3H), 7.54 (s, 1H), 8.43 (d, J=5.4 Hz, 1H) Mass spectrometric value(ESI-MS, m/z): 549 (M+1), 547 (M−1)

Compound 121

¹H-NMR (CDCl₃, 400 MHz): δ 0.94 (s, 9H), 1.43-1.49 (m, 2H), 1.88-2.06(m, 4H), 2.38-2.50 (m, 2H), 2.53-2.62 (m, 1H), 3.09-3.14 (m, 2H),3.26-3.34 (m, 4H), 4.01 (s, 3H), 4.41-4.46 (m, 2H), 4.87-4.93 (m, 1H),6.40 (d, J=5.1 Hz, 1H), 6.88 (br, 1H), 7.07 (d, J=9.0 Hz, 2H), 7.18-7.33(m, 5H), 7.42-7.50 (m, 3H), 7.55 (s, 1H), 8.42 (d, J=5.4 Hz, 1H) Massspectrometric value (ESI-MS, m/z): 597 (M+1), 595 (M−1)

Compound 122

¹H-NMR (CDCl₃, 400 MHz): δ 0.95 (s, 9H), 1.42-1.49 (m, 2H), 1.88-2.09(m, 4H), 2.26-2.47 (m, 4H), 2.55-2.66 (m, 1H), 2.83-2.92 (m, 2H),3.24-3.37 (m, 4H), 4.01 (s, 3H), 4.27 (t, J=6.3 Hz, 2H), 6.41 (d, J=5.4Hz, 1H), 7.08 (d, J=9.0 Hz, 2H), 7.19-7.34 (m, 5H), 7.38 (s, 1H), 7.47(d, J=8.8 Hz, 2H), 7.54 (s, 1H), 8.39 (d, J=5.1 Hz, 1H) Massspectrometric value (ESI-MS, m/z): 611 (M+1)

Compound 123

¹H-NMR (CDCl₃, 400 MHz): δ 0.94 (s, 9H), 1.42-1.50 (m, 4H), 1.62-1.74(m, 6H), 1.83-1.90 (m, 2H), 2.11-2.20 (m, 2H), 2.43 (br, 1H), 2.61 (br,4H), 2.93 (t, J=6.1 Hz, 2H), 3.08-3.15 (m, 2H), 3.25-3.33 (m, 2H), 4.00(s, 3H), 4.30 (t, J=6.1 Hz, 2H), 4.88-4.93 (m, 1H), 6.43 (d, J=5.4 Hz,1H), 6.88 (br, 1H), 7.10 (d, J=9.0 Hz, 2H), 7.40 (s, 1H), 7.43 (d, J=8.8Hz, 2H), 7.52 (s, 1H), 8.45 (d, J=5.4 Hz, 1H) Mass spectrometric value(ESI-MS, m/z): 604 (M+1)

Compound 124

¹H-NMR (CDCl₃, 400 MHz): δ 0.94 (s, 9H), 1.42-1.49 (m, 2H), 1.61-1.73(m, 2H), 1.76-1.98 (m, 4H), 2.13-2.25 (m, 2H), 2.64-2.71 (m, 3H), 2.93(t, J=6.0 Hz, 2H), 3.02-3.09 (m, 2H), 3.26-3.32 (m, 2H), 4.00 (s, 3H),4.31 (t, J=6.0 Hz, 2H), 4.90-4.95 (m, 1H), 6.42 (d, J=5.4 Hz, 1H), 6.88(br, 1H), 7.09 (d, J=9.0 Hz, 2H), 7.41 (d, J=5.6 Hz, 2H), 7.44 (s, 1H),7.52 (s, 1H), 8.44 (d, J=5.1 Hz, 1H) Mass spectrometric value (ESI-MS,m/z): 590 (M+1)

Compound 125

¹H-NMR (CDCl₃, 400 MHz): 0.97 (s, 9H), 1.17 (s, 3H), 1.19 (s, 3H),1.46-1.54 (m, 2H), 1.91-1.99 (m, 2H), 2.84-2.96 (m, 4H), 3.28-3.36 (m,2H), 3.68-3.78 (m, 2H), 4.01 (s, 3H), 4.33 (t, J=6.1 Hz, 2H), 4.76 (br,1H), 6.48 (d, J=5.4 Hz, 1H), 6.72 (br, 1H), 7.10 (dd, J=2.7, 9.0 Hz,1H), 7.21 (d, J=2.7 Hz, 1H), 7.42 (s, 1H), 7.50 (s, 1H), 8.26 (d, J=9.0Hz, 1H), 8.05 (d, J=5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z):607 (M+Na)⁺

Compound 126

¹H-NMR (CDCl₃, 400 MHz): 0.93 (s, 9H), 1.40-1.48 (m, 2H), 2.60-2.66 (m,4H), 2.94 (t, J=6.1 Hz, 2H), 3.25-3.34 (m, 2H), 3.72-3.78 (m, 4H), 4.02(s, 3H), 4.32 (t, J=5.9 Hz, 2H), 5.13 (br, 1H), 6.29 (d, J=6.1 Hz, 1H),7.11 (d, J=8.8 Hz, 1H), 7.31 (dd, J=2.7, 8.8 Hz, 1H), 7.40 (s, 1H), 7.42(br, 1H), 7.59 (s, 1H), 7.63 (d, J=2.7 Hz, 1H), 8.44 (d, J=5.1 Hz, 1H)Mass spectrometric value (ESI-MS, m/z): 579 (M+Na)⁺

Compound 127

¹H-NMR (CDCl₃, 400 MHz): 0.95 (s, 9H), 1.17 (s, 3H), 1.18 (s, 3H),1.42-1.50 (m, 2H), 1.90-1.98 (m, 2H), 2.85-2.95 (m, 4H), 3.26-3.35 (m,2H), 3.67-3.77 (m, 2H), 4.03 (s, 3H), 4.33 (t, J=5.9 Hz, 2H), 4.82 (br,1H), 6.30 (d, J=5.4 Hz, 1H), 6.88 (br, 1H), 7.14 (d, J=8.8 Hz, 1H), 7.31(dd, J=2.7, 8.8 Hz, 1H), 7.42 (s, 1H), 7.59 (s, 1H), 7.64 (d, J=2.7 Hz,1H), 8.45 (d, J=5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 607(M+Na)⁺

Compound 128

¹H-NMR (CDCl₃, 400 MHz): δ 0.95 (s, 9H), 1.18 (d, J=6.3 Hz, 6H),1.44-1.50 (m, 2H), 1.99 (t, J=10.9 Hz, 2H), 2.90-2.98 (m, 4H), 3.24-3.33(m, 2H), 3.71-3.80 (m, 2H), 4.02 (s, 3H), 4.36 (t, J=6.0 Hz, 2H),4.90-4.95 (m, 1H), 6.39 (d, J=5.4 Hz, 1H), 7.04-7.13 (m, 3H), 7.44 (s,1H), 7.50-7.55 (m, 1H), 7.58 (s, 1H), 8.42 (d, J=5.4 Hz, 1H) Massspectrometric value (ESI-MS, m/z): 569 (M+1)

Compound 129

¹H-NMR (CDCl₃, 400 MHz): δ 0.93 (s, 9H), 1.41-1.51 (m, 4H), 1.63-1.70(m, 4H), 2.57-2.64 (m, 4H), 2.96 (t, J=6.0 Hz, 2H), 3.25-3.32 (m, 2H),4.00 (s, 3H), 4.34 (t, J=6.0 Hz, 2H), 5.21-5.26 (m, 1H), 6.36 (d, J=5.4Hz, 1H), 7.04-7.07 (m, 2H), 7.40 (s, 1H), 7.49-7.55 (m, 2H), 7.57 (s,1H), 8.43 (d, J=5.4 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 539(M+1)

Compound 130

¹H-NMR (CDCl₃, 400 MHz): 0.92 (s, 9H), 1.18 (d, J=6.3 Hz, 6H), 1.19-1.75(m, 8H), 2.55-2.61 (m, 2H), 3.17-3.31 (m, 4H), 3.98 (s, 3H), 4.16-4.19(m, 2H), 5.07-5.09 (m, 1H), 6.44 (d, J=5.3 Hz, 1H), 6.82-6.95 (m, 3H),7.39 (s, 1H), 7.46 (s, 1H), 8.18 (t, J=9.0 Hz, 1H), 8.46 (d, J=5.3 Hz,1H) Mass spectrometric value (ESI-MS, m/z): 567 (M⁺+1)

Compound 131

¹H-NMR (CDCl₃, 400 MHz): 0.88 (s, 9H), 1.12 (s, 12H), 1.32-1.52 (m, 8H),2.95-3.00 (m, 2H), 3.21-3.27 (m, 2H), 3.96 (s, 3H), 4.00-4.17 (m, 2H),5.03-5.06 (m, 1H), 6.39 (d, J=5.4 Hz, 1H), 6.77-6.93 (m, 3H), 7.36 (s,1H), 7.42 (s, 1H), 8.11 (t, J=9.0 Hz, 1H), 8.41 (d, J=5.4 Hz, 1H) Massspectrometric value (ESI-MS, m/z): 595 (M⁺+1)

Compound 132

¹H-NMR (CDCl₃, 400 MHz): 0.90 (s, 9H), 1.17 (d, J=6.3 Hz, 6H), 1.27-1.67(m, 8H), 2.54-2.61 (m, 2H), 3.16-3.23 (m, 2H), 3.24-3.29 (m, 2H), 3.99(s, 3H), 4.02-4.18 (m, 2H), 5.15-5.18 (m, 1H), 6.36 (d, J=5.4 Hz, 1H),7.03-7.09 (m, 2H), 7.37 (s, 1H), 7.54 (s, 1H), 7.46-7.50 (m, 1H), 7.64(brs, 1H), 8.42 (d, J=5.4 Hz, 1H) Mass spectrometric value (ESI-MS,m/z): 567 (M⁺+1)

Compound 133

¹H-NMR (CDCl₃, 400 MHz): δ 0.94 (s, 3H), 0.98 (s, 3H), 0.95-1.12 (m,2H), 1.33-1.40 (m, 1H), 1.50-1.65 (m, 2H), 1.71-1.77 (m, 1H), 2.03-2.10(m, 1H), 2.61-2.66 (m, 4H), 2.95 (t, J=5.9 Hz, 2H), 3.70-3.88 (m, 6H),4.00 (s, 3H), 4.33 (t, J=5.9 Hz, 2H), 4.94 (d, J=7.8 Hz, 1H), 6.48 (d,J=5.1 Hz, 1H), 6.79 (d, J=2.6 Hz, 1H), 6.91 (dd, J=2.6, 11.5 Hz, 1H),6.96 (d, J=9.0 Hz, 1H), 7.41 (s, 1H), 7.50 (s, 1H), 8.20 (t, J=9.0 Hz,1H), 8.48 (d, J=5.1 Hz, 1H) Mass spectrometric value (ESI-MS, m/z): 565(M−1)

Compound 134

¹H-NMR (CDCl₃, 400 MHz): δ 0.93 (s, 3H), 0.98 (s, 3H), 0.94-1.11 (m,2H), 1.17 (d, J=9.3 Hz, 6H), 1.33-1.38 (m, 1H), 1.46-1.65 (m, 2H),1.70-1.76 (m, 1H), 1.94 (t, J=10.7 Hz, 2H), 2.04-2.14 (m, 2H), 2.86-2.95(m, 4H), 3.68-3.87 (m, 3H), 4.01 (s, 3H), 4.32 (t, J=5.9 Hz, 2H), 5.05(d, J=8.1 Hz, 1H), 6.47 (d, J=5.1 Hz, 1H), 6.86-6.98 (m, 3H), 7.41 (s,1H), 7.51 (s, 1H), 8.21 (t, J=9.0 Hz, 1H), 8.48 (d, J=5.1 Hz, 1H) Massspectrometric value (ESI-MS, m/z): 595 (M+1)

The following compounds were synthesized in the same manner as in theSynthesis Examples of the above compounds.

Compound No. Name of Compound

-   135:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2-nitro-phenyl]-3-(3,3-dimethyl-butyl)-urea-   136:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2-methyl-phenyl]-3-(3,3-dimethyl-butyl)-urea-   137:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-methyl-phenyl]-3-(3,3-dimethyl-butyl)-urea-   138:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2-methoxy-phenyl]-3-(3,3-dimethyl-butyl)-urea-   139:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-methoxy-phenyl]-3-(3,3-dimethyl-butyl)-urea-   140:    1-[3,5-Dichloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   141:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2,3-dimethyl-phenyl]-3-(3,3-dimethyl-butyl)-urea-   142:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2,5-dimethyl-phenyl]-3-(3,3-dimethyl-butyl)-urea-   143:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-phenyl]-3-(1,1,3,3-tetramethyl-butyl)-urea-   144:    1-[2-Chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-(1,1,3,3-tetramethyl-butyl)-urea-   145:    1-[4-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   146:    1-{4-[7-(2-Bromo-ethoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   147:    1-{4-[7-(3-Bromo-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   148:    1-{4-[7-(4-Bromo-butoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   149:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-3-(3,3,5,5-tetramethyl-hexyl)-urea-   150:    1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-2-trifluoromethyl-phenyl]-3-(3,3-dimethyl-butyl)-urea-   151:    1-{4-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   152:    1-{4-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   153:    1-{4-[7-(4-Chloro-butoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   154:    1-(3,3-Dimethyl-butyl)-3-{4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-urea    hydrochloride-   155:    1-(3,3-Dimethyl-butyl)-3-{4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-urea    hydrochloride-   156:    1-(3,3-Dimethyl-butyl)-3-(4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-urea    hydrochloride-   157:    1-(3,3-Dimethyl-butyl)-3-{4-[6-methoxy-7-(4-piperidin-1-yl-butoxy)-quinolin-4-yloxy]-phenyl}-urea    hydrochloride-   158:    1-(3,3-Dimethyl-butyl)-3-{4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-urea    hydrochloride-   159:    1-(3,3-Dimethyl-butyl)-3-(4-{6-methoxy-7-[4-(4-methyl-piperazin-1-yl)-butoxy]-quinolin-4-yloxy}-phenyl)-urea    hydrochloride-   160:    1-{2-Chloro-4-[7-(2-chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   161:    1-{2-Chloro-4-[7-(3-chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   162:    1-{2-Chloro-4-[7-(4-chloro-butoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   163:    1-[4-(7-Benzyloxy-6-methoxy-quinolin-4-yloxy)-2-chloro-phenyl]-3-(3,3-dimethyl-butyl)-urea-   164:    1-(2-Chloro-4-{7-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   165:    1-{2-Chloro-4-[6-methoxy-7-(2-pyrrolidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   166:    1-{2-Chloro-4-[7-(2-dimethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   167:    1-{2-Chloro-4-[7-(2-diethylamino-ethoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   168:    1-{2-Chloro-4-[6-methoxy-7-(piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   169:    1-{2-Chloro-4-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   170:    1-(2-Chloro-4-{7-[1-(2-hydroxy-ethyl)-piperidin-4-ylmethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   171:    1-(2-Chloro-4-{6-methoxy-7-[1-(2-methoxy-ethyl)-piperidin-4-ylmethoxy]-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   172:    1-{2-Chloro-4-[7-(3-dimethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   173:    1-(2-Chloro-4-{7-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   174:    1-(2-Chloro-4-{7-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   175:    1-{4-[7-(4-Amino-butoxy)-6-methoxy-quinolin-4-yloxy]-2-chloro-phenyl}-3-(3,3-dimethyl-butyl)-urea-   176:    1-[4-(7-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-2-chloro-phenyl]-3-(3,3-dimethyl-butyl)-urea-   177:    1-[2-Chloro-4-(7-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   178:    1-[2-Chloro-4-(7-{3-[(2-hydroxy-ethyl)-methyl-amino]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   179:    1-{2-Chloro-4-[6-methoxy-7-(3-pyrrolidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   180:    1-{2-Chloro-4-[6-methoxy-7-(3-piperidin-1-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   181:    1-{4-[7-(3-Azepan-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-2-chloro-phenyl}-3-(3,3-dimethyl-butyl)-urea-   182:    1-{2-Chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   183:    1-{2-Chloro-4-[7-(3-diethylamino-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   184:    1-[4-(7-{3-[Bis-(2-hydroxy-ethyl)-amino]-propoxy}-6-methoxy-quinolin-4-yloxy)-2-chloro-phenyl]-3-(3,3-dimethyl-butyl)-urea-   185:    1-{4-[7-(2-Azepan-1-yl-ethoxy)-6-methoxy-quinolin-4-yloxy]-2-chloro-phenyl}-3-(3,3-dimethyl-butyl)-urea-   186:    1-(2-Chloro-4-{6-methoxy-7-[2-(4-methyl-[1,4]diazepan-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   187:    1-(2-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   188:    1-(2-Chloro-4-{6-methoxy-7-[3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   189: Tert-butyl    3-(4-{3-chloro-4-[3-(3,3-dimethyl-butyl)-ureido]-phenoxy}-6-methoxy-quinolin-7-yloxymethyl)-piperidin-1-carboxylate-   190:    1-{2-Chloro-4-[6-methoxy-7-(piperidin-3-ylmethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   191:    1-{2-Chloro-4-[7-(3-diethylamino-2-hydroxy-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   192:    1-{2-Chloro-4-[7-(2-hydroxy-3-pyrrolidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   193:    1-{2-Chloro-4-[7-(2-hydroxy-3-piperidin-1-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   194:    1-{4-[7-(3-Azepan-1-yl-2-hydroxy-propoxy)-6-methoxy-quinolin-4-yloxy]-2-chloro-phenyl}-3-(3,3-dimethyl-butyl)-urea-   195:    1-{2-Chloro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   196:    1-(2-Chloro-4-{7-[2-hydroxy-3-(4-methyl-[1,4]diazepan-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   197:    1-{2-Chloro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   198:    1-{2-Chloro-4-[7-(3-ethylamino-2-hydroxy-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   199:    1-{2-Chloro-4-[7-(3-dimethylamino-2-hydroxy-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   200:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(2,6-dimethyl-morpholin-4-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   201:    1-{2-Chloro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   202:    1-{2-Chloro-4-[6-methoxy-7-(2-piperidin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   203:    1-{2-Chloro-4-[6-methoxy-7-(2-piperidin-2-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   204:    1-{4-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-2-fluoro-phenyl}-3-(3,3-dimethyl-butyl)-urea-   205:    1-{2-Chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   206:    1-{2-Chloro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   207:    1-(2-Chloro-4-{6-methoxy-7-[3-(4-methyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   208:    1-(2-Chloro-4-{7-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   209:    1-(3,3-Dimethyl-butyl)-3-{2-fluoro-4-[7-(2-hydroxy-3-morpholin-4-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-urea-   210:    1-(3,3-Dimethyl-butyl)-3-{2-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-urea-   211:    1-{2-Chloro-4-[7-(2-hydroxy-ethoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   212:    (4-Tert-butyl-phenyl)-{4-[7-methoxy-6-(2-morpholin-4-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-amine-   213:    1-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-7-methoxy-quinolin-6-yloxy}-3-morpholin-4-yl-propan-2-ol-   214:    4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-7-methoxy-quinolin-6-ol-   215: Methyl    (4-{4-[3-(3,3-dimethyl-butyl)-ureido]-phenoxy}-6-methoxy-quinolin-7-yloxy)-acetate-   216:    1-(3-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-ol-   217:    [1-(3-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-methanol-   218:    2-[1-(3-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-ethanol-   219:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   220:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{3-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   221:    (4-{4-[3-(3,3-Dimethyl-butyl)-ureido]-phenoxy}-6-methoxy-quinolin-7-yloxy)-acetic    acid-   222:    1-{4-[6-(2-Dimethylamino-ethoxy)-7-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   223:    1-(3,3-Dimethyl-butyl)-3-{4-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-urea-   224:    1-{4-[6-(3-Dimethylamino-propoxy)-7-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   225:    1-(3,3-Dimethyl-butyl)-3-{4-[6-(2-hydroxy-3-morpholin-4-yl-propoxy)-7-methoxy-quinolin-4-yloxy]-phenyl}-urea-   226:    1-{4-[6-(3-Dimethylamino-2-hydroxy-propoxy)-7-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   227:    1-(3,3-Dimethyl-butyl)-3-{4-[7-methoxy-6-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-urea-   228:    1-{4-[6-(4-Dimethylamino-butoxy)-7-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   229:    2-{4-[4-(4-Isopropyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-1-morpholin-4-yl-ethanone-   230:    4-{4-[3-(3,3-Dimethyl-butyl)-ureido]-3-fluoro-phenoxy}-6-methoxy-quinolin-7-yl    [1,4′]bipiperidineyl-1′-carboxylate-   231:    1-(3,3-Dimethyl-butyl)-3-(4-{6-[3-(2,6-dimethyl-morpholin-4-yl)-propoxy]-7-methoxy-quinolin-4-yloxy}-3-fluoro-phenyl)-urea-   232:    (4-Tert-butyl-phenyl)-(4-{7-[3-(2,6-dimethyl-morpholin-4-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-amine-   233:    (4-Tert-butyl-phenyl)-(4-{7-[3-(3,5-dimethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-amine-   234:    (4-Tert-butyl-phenyl)-(4-{6-methoxy-7-[3-(4-phenyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amine-   235:    (4-{7-[3-(4-Benzyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-(4-tert-butyl-phenyl)-amine-   236: {4-[7-(3-[1,4′]Bipiperidineyl-1    ′-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-(4-tert-butyl-phenyl)-amine-   237:    (4-Tert-butyl-phenyl)-(4-{6-methoxy-7-[3-(4-pyrrolidin-1-yl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-amine-   238:    (4-Tert-butyl-phenyl)-(4-{7-[2-(2,6-dimethyl-morpholin-4-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-amine-   239:    (4-Tert-butyl-phenyl)-(4-{7-[2-(3,5-dimethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-amine-   240:    (4-Tert-butyl-phenyl)-(4-{6-methoxy-7-[2-(4-phenyl-piperidin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-amine-   241:    (4-{7-[2-(4-Benzyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-(4-tert-butyl-phenyl)-amine-   242:    {4-[7-(2-[1,4′]Bipiperidineyl-1′-yl-ethoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-(4-tert-butyl-phenyl)-amine-   243:    (4-Tert-butyl-phenyl)-(4-{6-methoxy-7-[2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-amine-   244:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(2,6-dimethyl-morpholin-4-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   245:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(3,5-dimethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   246:    1-(3,3-Dimethyl-butyl)-3-(4-{6-methoxy-7-[3-(4-phenyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-urea-   247:    1-(4-{7-[3-(4-Benzyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   248:    1-{4-[7-(3-[1,4′]Bipiperidinyl-1′-yl-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   249:    1-(3,3-Dimethyl-butyl)-3-(4-{6-methoxy-7-[3-(4-pyrrolidin-1-yl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-urea-   250:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(2,6-dimethyl-morpholin-4-yl)-2-hydroxy-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   251:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(3,5-dimethyl-piperidin-1-yl)-2-hydroxy-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   252:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-hydroxy-3-(4-phenyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   253:    1-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-3-(2,6-dimethyl-morpholin-4-yl)-propan-2-ol-   254:    1-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-3-(3,5-dimethyl-piperidin-1-yl)-propan-2-ol-   256:    1-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-3-(4-phenyl-piperidin-1-yl)-propan-2-ol-   257:    1-(4-Benzyl-piperidin-1-yl)-3-{4-[4-(4-tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-propan-2-ol-   258:    1-[1,4′]Bipiperidineyl-1′-yl-3-{4-[4-(4-tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-propan-2-ol-   259:    1-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-3-(4-pyrrolidin-1-yl-piperidin-1-yl)-propan-2-ol-   260:    1-(4-{7-[3-(4-Benzyl-piperidin-1-yl)-2-hydroxy-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   261:    1-{4-[7-(3-[1,4′]Bipiperidineyl-1′-yl-2-hydroxy-propoxy)-6-methoxy-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   262:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-hydroxy-3-(4-pyrrolidin-1-yl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   263:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   265:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   266:    1-(2-Chloro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   267:    1-[2-Chloro-4-(7-{3-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   268:    1-(2-Chloro-4-{7-[3-(4-hydroxy-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   269:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{3-[(2-hydroxy-ethyl)-methyl-amino]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   270:    [1-(3-{4-[4-(4-Tert-butyl-phenylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-methanol-   271:    1-(3,3-Dimethyl-butyl)-3-(4-{6-methoxy-7-[3-(2-methoxy-ethylamino)-propoxy]-quinolin-4-yloxy}-phenyl)-urea-   272:    2-[1-(3-{4-[4-(4-Tert-butyl-phenylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-ethanol-   273:    1-(3-{4-[4-(4-Tert-butyl-phenylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-ol-   274:    1-(2-Chloro-4-{7-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   275:    1-(2-Chloro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   276:    1-(3-{4-[4-(4-Tert-butyl-phenylamino)-3-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-ol-   277:    [1-(3-{4-[4-(4-Tert-butyl-phenylamino)-3-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-methanol-   278:    1-(2-{4-[4-(4-Tert-butyl-phenylamino)-3-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-ol-   279:    [1-(2-{4-[4-(4-Tert-butyl-phenylamino)-3-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-yl]-methanol-   280:    (4-Tert-butyl-phenyl)-(4-{6-methoxy-7-[2-(4-methoxy-piperidin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-amine-   281:    (4-Tert-butyl-phenyl)-(4-{6-methoxy-7-[2-(4-methoxymethyl-piperidin-1-yl)-ethoxy]-quinolin-4-yloxy}-phenyl)-amine-   282:    1-(3,3-Dimethyl-butyl)-3-(4-{6-methoxy-7-[3-(4-methoxymethyl-piperidin-1-yl)-propoxy]-quinolin-4-yloxy}-phenyl)-urea-   283:    [1-(2-{4-[4-(4-Tert-butyl-phenylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-yl]-methanol-   284:    1-(2-{4-[4-(4-Tert-butyl-phenylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-ol-   285:    1-(3,3-Dimethyl-butyl)-3-(3-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   286:    1-(3,3-Dimethyl-butyl)-3-(3-fluoro-4-{7-[3-(4-hydroxy-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   287:    1-(2-{4-[4-(4-Tert-butyl-phenylamino)-3-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-ol-   288:    [1-(2-{4-[4-(4-Tert-butyl-phenylamino)-3-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-yl]-methanol-   289:    1-(3-{4-[4-(4-Tert-butyl-phenylamino)-3-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-ol-   290:    [1-(3-{4-[4-(4-Tert-butyl-phenylamino)-3-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-methanol-   292:    1-[2-Chloro-4-(7-{2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   293:    2-[1-(2-{4-[4-(4-Tert-butyl-phenylamino)-3-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-yl]-ethanol-   294:    2-[1-(3-{4-[4-(4-Tert-butyl-phenylamino)-3-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-ethanol-   295:    1-(3,3-Dimethyl-butyl)-3-(3-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   296:    1-(3,3-Dimethyl-butyl)-3-(3-fluoro-4-{7-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   297:    1-(3,3-Dimethyl-butyl)-3-[3-fluoro-4-(7-{2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   298:    1-(3,3-Dimethyl-butyl)-3-[3-fluoro-4-(7-{3-[4-(2-hydroxy-ethyl)-1-piperidin-1-yl]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   299:    1-(3,3-Dimethyl-butyl)-3-(2-fluoro-4-{7-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   300:    1-(3,3-Dimethyl-butyl)-3-(2-fluoro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   301:    1-(3,3-Dimethyl-butyl)-3-[2-fluoro-4-(7-{2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   302:    1-(3,3-Dimethyl-butyl)-3-(2-fluoro-4-{7-[3-(4-hydroxy-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   303:    1-(3,3-Dimethyl-butyl)-3-(2-fluoro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   304:    1-(3,3-Dimethyl-butyl)-3-[2-fluoro-4-(7-{3-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   305:    2-[1-(2-{4-[4-(4-Tert-butyl-phenylamino)-3-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-yl]-ethanol-   306:    2-[1-(3-{4-[4-(4-Tert-butyl-phenylamino)-3-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-ethanol-   307:    1-(2-{4-[4-(4-Tert-butyl-phenylamino)-2-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-ol-   308:    [1-(2-{4-[4-(4-Tert-butyl-phenylamino)-2-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-yl]-methanol-   309:    1-(3-{4-[4-(4-Tert-butyl-phenylamino)-2-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-ol-   310:    [1-(3-{4-[4-(4-Tert-butyl-phenylamino)-2-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-methanol-   311:    1-(3-Chloro-4-{7-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   312:    1-(3-Chloro-4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   313:    2-[1-(2-{4-[4-(4-Tert-butyl-phenylamino)-2-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-piperidin-4-yl]-ethanol-   314:    2-[1-(3-{4-[4-(4-Tert-butyl-phenylamino)-2-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-propyl)-piperidin-4-yl]-ethanol-   315:    1-[3-Chloro-4-(7-{2-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   316:    1-[3-Chloro-4-(7-{3-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   317:    1-(2-Chloro-4-{7-[3-(2,6-dimethyl-morpholin-4-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   318:    1-{3-Chloro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   319:    1-(3-Chloro-4-{7-[3-(2,6-dimethyl-morpholin-4-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   320:    1-{2-Chloro-4-[6-methoxy-7-(4-morpholin-4-yl-butoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3-dimethyl-butyl)-urea-   321:    1-(2-Chloro-4-{7-[4-(2,6-dimethyl-morpholin-4-yl)-butoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   322:    1-(3,3-Dimethyl-butyl)-3-(4-{6-[3-(4-hydroxy-piperidin-1-yl)-propoxy]-7-methoxy-quinolin-4-yloxy}-phenyl)-urea-   323:    1-(3,3-Dimethyl-butyl)-3-(4-{6-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-7-methoxy-quinolin-4-yloxy}-phenyl)-urea-   324:    1-(3,3-Dimethyl-butyl)-3-[4-(6-{3-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-propoxy}-7-methoxy-quinolin-4-yloxy)-phenyl]-urea-   325:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(2,6-dimethyl-morpholin-4-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-2-fluoro-phenyl)-urea-   326:    1-(3,3-Dimethyl-butyl)-3-{3-fluoro-4-[6-methoxy-7-(3-morpholin-4-yl-propoxy)-quinolin-4-yloxy]-phenyl}-urea-   327:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[3-(2,6-dimethyl-morpholin-4-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-3-fluoro-phenyl)-urea-   328:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   329:    1-(3,3-Dimethyl-butyl)-3-(2-fluoro-4-{7-[2-(2-hydroxy-ethylamino)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   330:    1-(3,3-Dimethyl-butyl)-3-[2-fluoro-4-(7-{2-[(2-hydroxy-ethyl)-methyl-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   331:    1-(2-Chloro-4-{7-[2-(2-hydroxy-ethylamino)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   332:    1-(3,3-Dimethyl-butyl)-3-(2-fluoro-4-{7-[3-(2-hydroxy-ethylamino)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   333:    1-(3,3-Dimethyl-butyl)-3-[2-fluoro-4-(7-{3-[(2-hydroxy-ethyl)-methyl-amino]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   334:    1-(2-Chloro-4-{7-[3-(2-hydroxy-ethylamino)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   335:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-3-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-(2-hydroxy-ethyl)-amino]-ethanol-   336:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-2-fluoro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-(2-hydroxy-ethyl)-amino]-ethanol-   337:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-3-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-(2-hydroxy-ethyl)-amino]-ethanol-   338:    1-(3-Chloro-4-{7-[3-(4-hydroxy-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   339:    1-(3-Chloro-4-{7-[3-(4-hydroxymethyl-piperidin-1-yl)-propoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   340:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{2-[ethyl-(2-hydroxy-ethyl)-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   341:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{2-[ethyl-(2-hydroxy-ethyl)-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-urea-   342:    1-[2-Chloro-4-(7-{2-[ethyl-(2-hydroxy-ethyl)-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   343:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   344:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propoxy}-6-methoxy-quinolin-4-yloxy)-2-fluoro-phenyl]-urea-   345:    1-[2-Chloro-4-(7-{3-[ethyl-(2-hydroxy-ethyl)-amino]-propoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   346:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-2-chloro-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-(2-hydroxy-ethyl)-amino]-ethanol-   347:    N1-[4-(Tert-butyl)phenyl]-4-[(6-methoxy-7-{2-[(tetrahydro-2-furanylmethyl)amino]ethoxy}-4-quinolyl)oxy]aniline-   348:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-methyl-amino]-ethanol    hydrochloride-   349:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-(2-hydroxy-ethyl)-amino]-ethanol    hydrochloride-   350:    [1-(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethylamino)-cyclopenthyl]-methanol-   351:    2-(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethylamino)-2-ethyl-propan-1,3-diol-   352:    1-[(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-(2-hydroxy-propyl)-amino]-propan-2-ol-   353:    2-(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethylamino)-propan-1-ol-   354:    1-(4-{7-[2-(1,1-Bis-hydroxymethyl-propylamino)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-3-(3,3-dimethyl-butyl)-urea-   355:    [1-(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-7-methoxy-quinolin-6-yloxy}-ethyl)-piperidin-4-yl]-methanol-   356:    2-(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-7-methoxy-quinolin-6-yloxy}-ethylamino)-ethanol-   357:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-7-methoxy-quinolin-6-yloxy}-ethyl)-methyl-amino]-ethanol-   358:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-7-methoxy-quinolin-6-yloxy}-ethyl)-(2-hydroxy-ethyl)-amino]-ethanol-   359:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(1-hydroxymethyl-cyclopenthylamino)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   360:    1-[4-(7-{2-[Bis-(2-hydroxy-propyl)-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   361:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(2-hydroxy-1-methyl-ethylamino)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   362:    1-[4-(7-{2-[Cyclohexyl-(2-hydroxy-ethyl)-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   363:    N1-[4-(Tert-butyl)phenyl]-4-[(6-methoxy-7-{2-[(2-methoxy-1-methylethyl)amino]ethoxy}-4-quinolyl)oxy]aniline-   364:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-cyclohexyl-amino]-ethanol-   365:    2-[Benzyl-(2-{4-[4-(4-tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-amino]-ethanol-   366:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-propyl-amino]-ethanol-   367:    2-[(2-{4-[4-(4-Tert-butyl-phenylamino)-phenoxy]-6-methoxy-quinolin-7-yloxy}-ethyl)-isopropyl-amino]-ethanol-   368:    1-[4-(7-{2-[Benzyl-(2-hydroxy-ethyl)-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   369:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{2-[(2-hydroxy-ethyl)-propyl-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   370:    1-(3,3-Dimethyl-butyl)-3-[4-(7-{2-[(2-hydroxy-ethyl)-isopropyl-amino]-ethoxy}-6-methoxy-quinolin-4-yloxy)-phenyl]-urea-   371:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(4-hydroxymethyl-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   372:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(2-hydroxy-ethylamino)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   373:    1-(3,3-Dimethyl-butyl)-3-(4-{7-[2-(4-hydroxy-piperidin-1-yl)-ethoxy]-6-methoxy-quinolin-4-yloxy}-phenyl)-urea-   374:    1-[3-Chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3-dimethyl-butyl)-urea-   375:    1-(3,3-Dimethyl-butyl)-3-{4-[6-methoxy-7-(2-morpholin-4-yl-2-oxo-ethoxy)-quinolin-4-yloxy]-phenyl}-urea

Compounds 135 to 141, 165, 179, 180, 183, 202, 207, and 245 wereanalyzed by mass spectrometry. The results were as follows. Massspectrometric Compound No. value (m/z) 135 469 [M + 1] 136 438 [M + 1]137 438 [M + 1] 138 454 [M + 1] 139 454 [M + 1] 140 492 [M + 1] 141 452[M + 1] 165 541 [M + 1] 179 555 [M + 1] 180 569 [M + 1] 183 557 [M + 1]202 555 [M + 1] 207 583 [M + 1] 245 563 [M + 1]

Compounds 135 to 375 had the following respective chemical structures.Compound No. structure of compound 135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

256

257

258

259

260

261

262

263

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

324

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

The following compounds were synthesized in the same manner as in theSynthesis Examples of the above compounds. Compound No. Name of compound376: 1-[4-(6,7-Dimethoxy-quinolin-4- yloxy)-3-fluoro-phenyl]-3-(3,3-dimethyl-butyl)-urea hydrochloride 377: 1-[3-Chloro-4-(6,7-dimethoxy-quinolin-4-yloxy)-phenyl]-3-(3,3- dimethyl-cyclohexyl)-urea 378:1-[4-(6,7-Dimethoxy-quinolin-4- yloxy)-3-fluoro-phenyl]-3-(3,3-dimethyl-cyclohexyl)-urea 379: 1-[4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-fluoro-phenyl]-3-(3,3- dimethyl-cyclohexyl)-urea 380:1-[4-(6,7-Dimethoxy-quinolin-4- yloxy)-phenyl]-3-pentyl-urea 381:1-Cyclohexyl-3-[4-(6,7-dimethoxy- quinolin-4-yloxy)-phenyl]-urea 382:1-[4-(6,7-Dimethoxy-quinolin-4- yloxy)-phenyl]-3-(4,4-dimethyl-pentyl)-urea 383: 1-[4-(6,7-Dimethoxy-quinazolin-4-yloxy)-phenyl]-3-(3,3- dimethyl-butyl)-urea 384:1-(3,3-Dimethyl-cyclohexyl)-3-{3- fluoro-4-[6-methoxy-7-(2-piperidin-1-yl-ethoxy)-quinolin-4- yloxy]-phenyl}-urea 385:1-{3-Fluoro-4-[6-methoxy-7-(2- piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3,5- trimethyl-cyclohexyl)-urea 386:1-{2-Fluoro-4-[6-methoxy-7-(2- piperidin-1-yl-ethoxy)-quinolin-4-yloxy]-phenyl}-3-(3,3,5- trimethyl-cyclohexyl)-urea 387:1-{4-[7-(2-Azepan-1-yl-ethoxy)- 6-methoxy-quinolin-4-yloxy]-2-chloro-phenyl}-3-(3,3-dimethyl- butyl)-urea 388:1-(3,3-Dimethyl-butyl)-3-(4-{6- methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-urea hydrochloride389: 1-(3,3-Dimethyl-butyl)-3-(2-fluoro- 4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-urea 390:1-(3,3-Dimethyl-butyl)-3-(3-chloro- 4-{6-methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]- quinolin-4-yloxy}-phenyl)-urea

For these compounds, chemical structures, starting compounds, synthesismethods, and data for identifying the compounds are as follows. Thenumeral described in the column of the synthesis method indicates thatthe indicated compound has been synthesized according to the SynthesisExample of the indicated compound number. Compound No Structure ofcompound Starting compound A 376

377

378

379

380

Compound Starting Synthesis Mass spectrometric No. compound B methodvalue (m/z) 376

101 482 [M − 1]484 [M + 1] 377

101 496 [M − 1]498 [M + 1] 378

101 468 [M + 1]466 [M − 1] 379

101 482 [M + 1]480 [M − 1] 380

101 410 [M + 1] Com- pound No. Structure of compound Starting compound A381

382

383

384

385

Compound Synthesis Mass spectrometric No. Starting compound B methodvalue (m/z) 381

101 422 [M + 1] 382

101 438 [M + 1] 383

101 425 [M + 1] 384

99 565 [M + 1] 385

99 579 [M + 1] Compound No. Structure of compound 386

387

388

389

390

Compound No. Starting compound A 386

387

388

389

390

Compound Starting Synthesis Mass spectrometric No. compound B methodvalue (m/z) 386

99 579 [M + 1] 387

99 569 [M + 1] 388

99 550 [M + 1] 389

99 568 [M + 1] 390

99 584 [M + 1]

Pharmacological Test Example 1 Measurement of Inhibitory ActivityAgainst Bek-Autophosphorylation Using ELISA Method

Human scirrhus stomach cancer cells OCUM-2MD3 (kindly provided by Dr.Kosei Hirakawa, Osaka City University) were cultured in an RPMI mediumcontaining 10% fetal calf serum (purchased from ICN) within a 5% carbondioxide incubator until 50 to 90% confluent. The harvested cells wereseeded onto 96-well flat-bottom plate in RPMI containing 0.1% fetal calfserum at 3.5×10⁴ cells per well, followed by cultivation at 37° C.overnight. A solution of the test compound in dimethyl sulfoxide wasadded to each well, and the cultivation was continued at 37° C. foradditional one hr. The medium was removed, and 50 μl of lysis buffer (20mM HEPES (pH 7.4), 150 mM NaCl, 0.2% Triton X-100, 10% glycerol, 5 mMsodium orthovanadylate, 5 mM disodium ethylenediaminetetraacetate, and 2mM Na₄P₂O₇) was then added thereto. The mixture was shaken at 4° C. for2 hr to prepare cell extracts.

Separately, phosphate buffered saline (50 μl, pH 7.4) containing 5 g/mlof anti-phospho-tyrosine antibody (PY20; purchased from TransductionLaboratories) was added to a microplate for ELISA (Maxisorp; purchasedfrom NUNC), followed by standing at 4° C. overnight to form a solidphase on the wells. After washing of the plate, 300 μl of a blockingsolution was added, followed by standing at room temperature for 2 hr toperform blocking. After washing, the whole quantity of the cell extractswas transferred to the wells, and the plate was then allowed to stand at4° C. overnight. After washing, an anti-Bek antibody (Bek (C-17),purchased from Santa Cruz Biotechnology) or Anti-Human K-sam Rabbit IgGAffinity Purity (purchased from IBL Co., Ltd.) was allowed to react atroom temperature for one hr, and, after washing, a peroxidase-labeledanti-rabbit Ig antibody (purchased from Amersham) was allowed to reactat room temperature for one hr. After washing, a chromophoric substratefor peroxidase (purchased from Sumitomo Bakelite Co., Ltd.) was addedthereto to initiate a reaction. After a suitable level of colordevelopment, a reaction termination solution was added to stop thereaction, and the absorbance at 450 nm was measured with a microplatereader. The Bek-phosphorylation activity for each well was determined bypresuming the absorbance without the addition of the medicament to be100% Bek-phosphorylation activity and the absorbance with the additionof a large excess of a positive control(N-{4-[(6,7-dimethoxy-4-quinolyl)oxy]phenyl}-N′-(3,3-dimethylbutyl)urea,1000 nM) to be 0% Bek-phosphorylation activity. The concentration of thetest compound was varied on several levels, the Bek-phosphorylationinhibitory activity was determined for each case, and the concentrationof the test compound necessary for inhibiting 50% of Bek-phosphorylation(IC₅₀) was calculated. The results were as shown in Table 1. TABLE 1Compound No. IC50, uM 1 3.9286 2 7.9407 3 4.5819 4 3.7268 5 0.3209 60.8753 7 1.7965 8 1.5028 9 0.3127 10 0.6314 11 0.3199 12 0.2853 130.2791 14 1.9230 15 0.4298 16 0.2418 17 5.6149 18 0.1554 19 0.1946 200.3254 21 0.3279 22 0.1891 23 0.7617 24 0.1831 25 0.1994 26 0.3176 272.5210 28 2.4043 29 0.9310 30 3.2615 31 1.0087 32 0.6935 33 0.1554 340.2188 35 0.2205 36 0.2469 37 0.3449 38 0.4626 39 0.5703 40 0.9242 410.4799 42 0.3989 43 3.3410 44 0.0765 45 0.2403 46 0.2300 47 0.2433 480.0335 49 0.0339 50 0.0350 51 0.0306 52 0.0330 53 0.0380 54 0.3242 558.0027 56 0.4054 57 3.8267 58 1.1998 59 0.1427 60 0.2034 61 0.1865 620.2494 63 0.2466 64 0.1782 65 0.1845 66 0.1986 67 0.1885 68 0.2483 690.2477 70 0.0685 71 0.0611 72 0.8359 73 3.5085 74 0.5206 75 5.1890 767.5605 77 3.4479 78 0.2737 79 0.1587 80 0.1512 81 0.0101 82 0.0701 87<0.0100 88 0.0108 89 <0.0100 90 0.0126 91 0.0184 94 <0.0100 96 <0.010097 <0.0100 98 <0.0100 99 0.0286 100 0.1753 101 <0.0100 102 0.0278 1030.0298 105 0.0306 106 0.0197 107 <0.0100 108 <0.0100 109 <0.0100 110<0.0100 111 <0.0100 112 0.0521 113 0.01 114 0.0201 115 <0.0100 1160.0144 117 0.1778 119 <0.0100 120 0.021 121 0.088 122 0.1509 123 <0.0100124 <0.0100 125 0.013 126 0.0133 127 0.0094 128 <0.0100 129 0.0481 1300.1623 131 0.1607 132 0.1463 133 0.0092 134 0.0118 136 0.0562 137 0.0667138 0.3166 139 1.1584 140 0.1723 141 0.0586 142 0.2653 143 0.1925 1440.2018 147 0.6539 148 1.6713 149 0.2182 150 0.0638 151 0.2214 152 0.025153 0.2408 154 0.0244 155 0.0287 156 0.0191 157 0.0285 158 0.0321 1590.0262 160 0.0235 161 0.1887 162 0.2522 163 0.3696 164 0.2598 165 0.0689166 0.039 167 0.095 168 0.024 169 0.0252 170 0.0244 171 0.0324 172<0.0100 173 0.1526 175 0.0217 176 <0.0100 177 0.0106 178 <0.0100 1790.0173 180 0.0227 181 0.0262 182 0.0095 183 0.0154 184 0.0092 185 0.0548186 0.0183 187 0.0223 188 0.0299 189 0.0833 190 0.0335 191 0.0106 1920.0091 193 0.0174 194 0.0197 195 <0.0100 196 0.0173 197 <0.0100 1980.0123 199 <0.0100 200 0.0211 201 <0.0100 202 0.0285 203 0.0297 2040.2343 205 0.0255 206 0.0185 207 0.06 208 0.027 209 <0.0100 210 <0.0100211 <0.0100 212 0.1374 213 0.1255 214 0.0261 215 0.341 216 0.1741 2170.0409 218 0.096 219 <0.0100 220 0.012 221 0.7625 222 0.0243 223 0.0498224 0.0704 225 0.0199 226 0.0279 227 0.0239 228 0.0385 229 0.1559 2300.0321 231 0.1133 232 0.1029 233 0.3711 236 0.2688 237 0.2072 238 0.0472239 0.8949 242 0.4007 243 0.3415 244 <0.0100 245 0.0165 246 0.0309 2470.0819 248 0.0126 249 <0.0100 250 <0.0100 251 0.0207 252 0.0426 2530.0285 254 0.0942 258 0.11 259 0.0466 260 0.0267 261 <0.0100 262 <0.0100263 <0.0100 264 1.4351 265 <0.0100 266 0.011 267 0.0267 268 0.0157 2690.0356 270 0.303 271 0.0332 272 0.1512 273 0.1612 274 0.0278 275 0.0316276 1.1253 277 0.617 278 1.1247 279 0.3699 280 0.2784 281 0.2443 2820.0316 283 0.167 284 0.2467 285 0.0228 286 0.0172 287 0.2541 288 0.1095289 0.2482 290 0.2329 292 0.0496 293 2.3564 294 1.1001 295 0.0144 2960.0198 297 0.0424 298 0.0417 299 0.0274 300 0.0227 301 0.0384 302 0.0266303 0.022 304 0.0312 305 0.3593 306 0.2865 307 0.3792 308 0.2045 3090.2111 310 0.1837 311 0.0231 312 0.0205 313 0.3674 314 0.2772 315 0.1328316 0.0851 317 0.0204 318 0.0187 319 0.022 320 0.0214 321 0.0254 3220.247 323 0.3733 324 0.2868 325 0.0342 326 <0.0100 327 0.0206 328 0.037329 0.0208 330 0.0178 331 0.0301 332 0.0108 333 0.0094 334 0.0165 3350.0953 336 0.053 337 0.252 338 0.0166 339 0.0164 340 0.0183 341 0.0289342 0.0116 343 <0.0100 344 <0.0100 345 0.0098 346 0.2941 347 0.3541 3480.1862 349 0.0959 350 0.3342 351 0.2323 352 0.0547 353 0.3741 354 0.0384355 0.4027 356 0.3467 357 0.2131 358 0.0517 359 0.2542 360 0.0195 3610.0298 362 0.0492 363 0.3636 364 0.2301 365 7.1303 366 0.2571 367 0.4681368 0.1566 369 0.0423 370 0.1303 371 <0.0100 372 <0.0100 373 <0.0100 3740.0328 375 0.028

Pharmacological Test Example 2 Tumor Growth Inhibitory Activity againstHuman Gastric Cancer Cells (OCUM-2MD3)

Human gastric cancer cells (OCUM-2MD3) (kindly provided by Dr. KoseiHirakawa, Osaka City University) were transplanted into nude mice. Whenthe tumor volume became about 100 to 200 mm³, the mice were grouped sothat the groups each consisted of four mice and had an even averagetumor volume. The test compound suspended in 0.5% methylcellulose wasorally administered every day twice a day for 5 days (except for thefirst day on which the suspension was administered once a day).

Only 0.5% methylcellulose was administered to the control group in themanner as in the test groups. The tumor growth inhibition rate (TGIR)was calculated as follows: The tumor growth inhibition rate(TGIR)=(1−TX/CX)×100 wherein CX represents the volume of tumor at day Xfor the control group when the tumor volume at the day of the start ofthe administration was presumed to be 1; and TX represents the volume oftumor for test compound administration groups.

The tumor growth inhibition rate for representative examples of a groupof compounds according to the present invention is shown in Table 2.TABLE 2 Unit dose, mg/kg TGIR, % Compound 37 (hydrochloride) 10 35Compound 59 (hydrochloride) 10 16

Pharmacological Test Example 3 Tumor Growth Inhibitory Activity againstHuman Gastric Cancer Cells (OCUM-2MD3)

Tumor growth inhibitory activity was measured in the same manner as inPharmacological Test Example 2, except that oral administration wascarried out once a day or twice a day (except for the first day on whichthe suspension was administered once a day).

The tumor growth inhibition rate for representative examples of a groupof compounds according to the present invention is shown in Table 3.TABLE 3 Dose per day TGIR, % Compound 83 10 mg × 2 34 Compound 84 10 mg× 2 33 Compound 85 10 mg × 2 43 Compound 86 10 mg × 2 30 Compound 87 10mg × 2 33 Compound 87 25 mg × 1 54 Compound 88 10 mg × 2 35 Compound 8910 mg × 2 29 Compound 90 10 mg × 2 36 Compound 91 25 mg × 1 28 Compound94 10 mg × 2 40 Compound 97 25 mg × 1 48 Compound 98 25 mg × 1 48Compound 99 25 mg × 1 63 Compound 100 25 mg × 1 43 Compound 114 30 mg ×2 48

1. A compound represented by formula (I) or a pharmaceuticallyacceptable salt or solvate thereof:

wherein X represents CH or N; Z represents O or S; Q represents—N(—R¹⁰)— wherein R¹⁰ represents a hydrogen atom or C₁₋₄ alkyl,—C(—R¹¹)(—R¹²)— wherein R¹¹ and R¹², which may be the same or different,represent a hydrogen atom or C₁₋₆ alkylcarbonyloxy, —C(═O)—, —O—,—S(═O)m- wherein m is 0, 1, or 2, or —NH—C(═O)—NH—; R¹, R², and R³,which may be the same or different, represent a hydrogen atom, hydroxyl,a halogen atom, nitro, amino, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, orC₁₋₆ alkoxy, in which the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, andC₁₋₆ alkoxy groups, which may be represented by R¹, R², and R³, areoptionally substituted by hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆alkylcarbonyl; carboxyl; C₁₋₆ alkoxycarbonyl; —(C═O)—NR¹⁴R¹⁵ wherein R¹⁴and R¹⁵, which may be the same or different, represent a hydrogen atomor C₁₋₄ alkyl optionally substituted by hydroxyl, or alternatively R¹⁴and R¹⁵ may combine with the nitrogen atom attached thereto to form asaturated five- or six-membered heterocyclic group; amino in which oneor two hydrogen atoms on the amino group are optionally substituted byC₁₋₆ alkyl or a saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group, and the C₁₋₆ alkyl group isoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;or a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, an oxygen atom, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;when the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain; and the carbocyclic or heterocyclic group may becondensed with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic group to form a bicyclic group; one or twohydrogen atoms on the amino group, which may be represented by R¹, R²,and R³, are optionally substituted by C₁₋₆ alkyl which is optionallysubstituted by hydroxyl or C₁₋₆ alkoxy; R⁴ represents a hydrogen atom;R⁵, R⁶, R⁷, and R⁸, which may be the same or different, represent ahydrogen atom, a halogen atom, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro, or amino;and R⁹ represents C₁₋₁₀ alkyl or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group in which the three- toeight-membered carbocyclic or heterocyclic group is optionallysubstituted by an oxygen atom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₁₋₆ alkoxy, a halogen atom, or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group, and the C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, and C₁₋₆ alkoxy groups are optionallysubstituted by a halogen atom or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group, provided that, when Qrepresents —C(═O)—, R² and R³ do not simultaneously represent methoxy.2. The compound according to claim 1, wherein R¹ represents a hydrogenatom and R² and R³, which may be the same or different, represent agroup other than a hydrogen atom.
 3. The compound according to claim 1or 2, wherein R² represents unsubstituted C₁₋₆ alkoxy.
 4. The compoundaccording to any one of claims 1 to 3, wherein R³ represents hydroxyl oroptionally substituted C₁₋₆ alkoxy.
 5. The compound according to any oneof claims 1 to 4, wherein R³ represents —O—(CH₂)p-R¹³ wherein p is aninteger of 0 to 6, —(CH₂)p- is optionally substituted by C₁₋₆ alkyl,hydroxyl, or a halogen atom, and R¹³ represents a hydrogen atom;hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆ alkylcarbonyl; carboxyl;C₁₋₆ alkoxycarbonyl; —(C═O)—NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵, which may bethe same or different, represent a hydrogen atom or C₁₋₄ alkyloptionally substituted by hydroxyl, or alternatively R¹⁴ and R¹⁵ maycombine with the nitrogen atom attached thereto to form a saturatedfive- or six-membered heterocyclic group; amino in which one or twohydrogen atoms on the amino group are optionally substituted by C₁₋₆alkyl or a saturated or unsaturated three- to eight-membered carbocyclicor heterocyclic group, and the C₁₋₆ alkyl group is optionallysubstituted by hydroxyl, C₁₋₆ alkoxy, or a saturated or unsaturatedthree- to eight-membered carbocyclic or heterocyclic group; or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, an oxygen atom, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;when the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain; and the carbocyclic or heterocyclic group may becondensed with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic group to form a bicyclic group.
 6. Thecompound according to any one of claims 1 to 5, wherein all of R⁵, R⁶,R⁷, and R⁸ represent a hydrogen atom, or any one or two of R⁵, R⁶, R⁷,and R⁸ represent a group other than a hydrogen atom with all theremaining groups representing a hydrogen atom.
 7. The compound accordingto any one of claims 1 to 6, wherein R⁹ represents a saturated orunsaturated four- to seven-membered carbocyclic or heterocyclic group inwhich the four- to seven-membered carbocyclic or heterocyclic group isoptionally substituted by an oxygen atom, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄alkoxy, a halogen atom, or a saturated or unsaturated four- toseven-membered carbocyclic or heterocyclic group, and the C₁₋₄ alkyl,C₂₋₄ alkenyl, and C₁₋₄ alkoxy groups are optionally substituted by ahalogen atom or saturated or unsaturated four- to seven-memberedcarbocyclic or heterocyclic group.
 8. The compound according to any oneof claims 1 to 6, wherein R⁹ represents phenyl of which the p-positionis substituted by C₁₋₄ alkyl or a saturated or unsaturated four- toseven-membered carbocyclic or heterocyclic group.
 9. The compoundaccording to any one of claims 1 to 6, wherein R⁹ represents C₁₋₄ alkylsubstituted by t-butyl; or a saturated five- to seven-memberedcarbocyclic group optionally substituted by one, two, or three of C₁₋₄alkyl groups.
 10. The compound according to claim 1, wherein thecompound represented by formula (I) is a compound represented by formula(100):

wherein X represents CH or N; Q represents —N(—R¹¹⁰)— wherein R¹¹⁰represents a hydrogen atom or C₁₋₄ alkyl, —C(—R¹¹¹)(—R¹¹²)— wherein R¹¹¹and R¹¹², which may be the same or different, represent a hydrogen atomor C₁₋₄ alkylcarbonyloxy, or —O—; R¹⁰³ represents hydroxyl or C₁₋₆alkoxy in which the C₁₋₆ alkoxy group is optionally substituted byhydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆ alkylcarbonyl; carboxyl;C₁₋₆ alkoxycarbonyl; —(C═O)—NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵, which may bethe same or different, represent a hydrogen atom or C₁₋₄ alkyloptionally substituted by hydroxyl, or alternatively R¹⁴ and R¹⁵ maycombine with the nitrogen atom attached thereto to form a saturatedfive- or six-membered heterocyclic group; amino in which one or twohydrogen atoms on the amino group are optionally substituted by C₁₋₆alkyl or a saturated or unsaturated three- to eight-membered carbocyclicor heterocyclic group, and the C₁₋₆ alkyl group is optionallysubstituted by hydroxyl, C₁₋₆ alkoxy, or a saturated or unsaturatedthree- to eight-membered carbocyclic or heterocyclic group; or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, an oxygen atom, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;when the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain; and the carbocyclic or heterocyclic group may becondensed with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic group to form a bicyclic group; all of R¹⁰⁵,R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸ represent a hydrogen atom, or any one or two ofR¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸ represent a halogen atom, C₁₋₄ alkyl, C₁₋₄alkoxy, nitro, or amino with all the remaining groups representing ahydrogen atom; and R¹⁰⁹ represents a saturated or unsaturated four- toseven-membered carbocyclic or heterocyclic group in which the four- toseven-membered carbocyclic or heterocyclic group is optionallysubstituted by an oxygen atom, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₁₋₄ alkoxy, ahalogen atom, or a saturated or unsaturated four- to seven-memberedcarbocyclic or heterocyclic group, and the C₁₋₄ alkyl, C₂₋₄ alkenyl, andC₁₋₄ alkoxy groups are optionally substituted by a halogen atom orsaturated or unsaturated four- to seven-membered carbocyclic orheterocyclic group.
 11. The compound according to claim 1, wherein thecompound represented by formula (I) is represented by formula (200):

wherein X represents CH or N; R²⁰³ represents —O—(CH₂)p-R¹³ wherein p isan integer of 0 to 6, —(CH₂)p- is optionally substituted by C₁₋₆ alkyl,hydroxyl, or a halogen atom, and R¹³ represents a hydrogen atom;hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆ alkylcarbonyl; carboxyl;C₁₋₆ alkoxycarbonyl; —(C═O)—NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵, which may bethe same or different, represent a hydrogen atom or C₁₋₄ alkyloptionally substituted by hydroxyl, or alternatively R¹⁴ and R¹⁵ maycombine with the nitrogen atom attached thereto to form a saturatedfive- or six-membered heterocyclic group; C₁₋₆ alkoxycarbonyl; amino inwhich one or two hydrogen atoms on the amino group are optionallysubstituted by C₁₋₆ alkyl or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group, and the C₁₋₆ alkylgroup is optionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; or a saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group in which the carbocyclic orheterocyclic group is optionally substituted by hydroxyl, an oxygenatom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, or a saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group; the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl groups are optionally substituted by hydroxyl, C₁₋₆ alkoxy,or a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group; when the carbocyclic or heterocyclic group issubstituted by two C₁₋₆ alkyl groups, the two alkyl groups may combinetogether to form an alkylene chain; and the carbocyclic or heterocyclicgroup may be condensed with another saturated or unsaturated five- toseven-membered carbocyclic or heterocyclic group to form a bicyclicgroup; all of R²⁰⁵, R²⁰⁶, R²⁰⁷, and R²⁰⁸ represent a hydrogen atom, orany one or two of R²⁰⁵, R²⁰⁶, R²⁰⁷, and R²⁰⁸ represent a halogen atom,C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro, or amino with all the remaining groupsrepresenting a hydrogen atom; and R²⁰⁹ represents C₁₋₄ alkyl or asaturated or unsaturated four- to seven-membered carbocyclic orheterocyclic group and R²¹⁰ represents a hydrogen atom or C₁₋₄ alkyl.12. The compound according to claim 1, wherein the compound representedby formula (I) is represented by formula (300):

wherein X represents CH or N; R³⁰² represents —O—(CH₂)p-R¹³ wherein p isan integer of 0 to 6, —(CH₂)p- is optionally substituted by C₁₋₆ alkyl,hydroxyl, or a halogen atom, and R¹³ represents a hydrogen atom;hydroxyl; a halogen atom; C₁₋₆ alkoxy; C₁₋₆ alkylcarbonyl; carboxyl;C₁₋₆ alkoxycarbonyl; —(C═O)—NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵, which may bethe same or different, represent a hydrogen atom or C₁₋₄ alkyloptionally substituted by hydroxyl, or alternatively R¹⁴ and R¹⁵ maycombine with the nitrogen atom attached thereto to form a saturatedfive- or six-membered heterocyclic group; C₁₋₆ alkoxycarbonyl; amino inwhich one or two hydrogen atoms on the amino group are optionallysubstituted by C₁₋₆ alkyl or a saturated or unsaturated three- toeight-membered carbocyclic or heterocyclic group, and the C₁₋₆ alkylgroup is optionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; or a saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group in which the carbocyclic orheterocyclic group is optionally substituted by hydroxyl, an oxygenatom, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆alkoxycarbonyl, or a saturated or unsaturated three- to eight-memberedcarbocyclic or heterocyclic group; the C₁₋₆ alkyl, C₂₋₆ alkenyl, andC₂₋₆ alkynyl groups are optionally substituted by hydroxyl, C₁₋₆ alkoxy,or a saturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group; when the carbocyclic or heterocyclic group issubstituted by two C₁₋₆ alkyl groups, the two alkyl groups may combinetogether to form an alkylene chain; and the carbocyclic or heterocyclicgroup may be condensed with another saturated or unsaturated five- toseven-membered carbocyclic or heterocyclic group to form a bicyclicgroup; all of R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸ represent a hydrogen atom, orany one or two of R³⁰⁵, R³⁰⁶, R³⁰⁷, and R³⁰⁸ represent a halogen atom,C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro, or amino with all the remaining groupsrepresenting a hydrogen atom; and R³⁰⁹ represents C₁₋₄ alkyl or asaturated or unsaturated four- to seven-membered carbocyclic orheterocyclic group and R³¹⁰ represents a hydrogen atom or C₁₋₄ alkyl.13. The compound according to claim 1, wherein the compound representedby formula (I) is represented by formula (400):

wherein X represents CH or N; R⁴⁰² and R⁴⁰³, which may be the same ordifferent, represent —O—(CH₂)p-R¹³ wherein p is an integer of 0 to 6,—(CH₂)p- is optionally substituted by C₁₋₆ alkyl, hydroxyl, or a halogenatom, and R¹³ represents a hydrogen atom; hydroxyl; a halogen atom; C₁₋₆alkoxy; C₁₋₆ alkylcarbonyl; carboxyl; C₁₋₆ alkoxycarbonyl;—(C═O)—NR¹⁴R¹⁵ wherein R¹⁴ and R¹⁵, which may be the same or different,represent a hydrogen atom or C₁₋₄ alkyl optionally substituted byhydroxyl, or alternatively R¹⁴ and R¹⁵ may combine with the nitrogenatom attached thereto to form a saturated five- or six-memberedheterocyclic group; C₁₋₆ alkoxycarbonyl; amino in which one or twohydrogen atoms on the amino group are optionally substituted by C₁₋₆alkyl or a saturated or unsaturated three- to eight-membered carbocyclicor heterocyclic group, and the C₁₋₆ alkyl group is optionallysubstituted by hydroxyl, C₁₋₆ alkoxy, or a saturated or unsaturatedthree- to eight-membered carbocyclic or heterocyclic group; or asaturated or unsaturated three- to eight-membered carbocyclic orheterocyclic group in which the carbocyclic or heterocyclic group isoptionally substituted by hydroxyl, an oxygen atom, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, C₁₋₆ alkoxycarbonyl, or a saturatedor unsaturated three- to eight-membered carbocyclic or heterocyclicgroup; the C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl groups areoptionally substituted by hydroxyl, C₁₋₆ alkoxy, or a saturated orunsaturated three- to eight-membered carbocyclic or heterocyclic group;when the carbocyclic or heterocyclic group is substituted by two C₁₋₆alkyl groups, the two alkyl groups may combine together to form analkylene chain; and the carbocyclic or heterocyclic group may becondensed with another saturated or unsaturated five- to seven-memberedcarbocyclic or heterocyclic group to form a bicyclic group; all of R⁴⁰⁵,R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸ represent a hydrogen atom, or any one or two ofR⁴⁰⁵, R⁴⁰⁶, R⁴⁰⁷, and R⁴⁰⁸ represent a halogen atom, C₁₋₄ alkyl, C₁₋₄alkoxy, nitro, or amino with all the remaining groups representing ahydrogen atom; and R⁴⁰⁹ represents C₁₋₄ alkyl substituted by t-butyl; ora saturated five- to seven-membered carbocyclic group optionallysubstituted by one, two, or three of C₁₋₄ alkyl groups.
 14. Apharmaceutical composition comprising the compound according to any oneof claims 1 to 13 or a pharmaceutically acceptable salt or solvatethereof.
 15. The pharmaceutical composition according to claim 14, foruse in the treatment or prophylaxis of a disease for which theinhibition of Bek-autophosphorylation is effective therapeutically orprophylactically.
 16. The pharmaceutical composition according to claim15, wherein the disease for which the inhibition ofBek-autophosphorylation is effective therapeutically or prophylacticallyis a malignant tumor.
 17. The pharmaceutical composition according toclaim 16, wherein said malignant tumor is selected from the groupconsisting of gastric cancer, brain tumors, colon cancer, pancreaticcancer, lung cancer, renal cancer, ovarian cancer, and prostatic cancer.18. Use of the compound according to any one of claims 1 to 13 or apharmaceutically acceptable salt or solvate thereof, for the manufactureof an agent for use in the treatment or prophylaxis of a disease forwhich the inhibition of Bek-autophosphorylation is effectivetherapeutically or prophylactically.
 19. A method for treating orpreventing a disease for which the inhibition of Bek-autophosphorylationis effective therapeutically or prophylactically, said method comprisingthe step of administering a therapeutically or prophylacticallyeffective amount of the compound according to any one of claims 1 to 13or a pharmaceutically acceptable salt or solvate thereof to a mammal.